Hepatitis B antiviral agents

ABSTRACT

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof:X-A-Y-L-R  (I)which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/114,842, filed Aug. 28, 2018, which claims the benefit of U.S.Provisional Application No. 62/550,992, filed on Aug. 28, 2017. Theentire teachings of the above applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates generally to novel antiviral agents.Specifically, the present invention relates to compounds which caninhibit the protein(s) encoded by hepatitis B virus (HBV) or interferewith the function of the HBV life cycle, compositions comprising suchcompounds, methods for inhibiting HBV viral replication, methods fortreating or preventing HBV infection, and processes for making thecompounds.

BACKGROUND OF THE INVENTION

HBV infection remains a major public health problem, affectingapproximately 2 billion people worldwide. Among them, 350 million peopleworldwide and 1.4 million in the US develop a chronic infection, whichcan lead to chronic persistent hepatitis, liver cirrhosis, andhepatocellular carcinoma (HCC). Every year 500,000 to 1 million peopledie from the end stage of liver diseases caused by HBV infection.

Despite the availability of a prophylactic HBV vaccine, the burden ofchronic HBV infection continues to be a significant unmet worldwidemedical problem, due to suboptimal treatment options and sustained ratesof new infections in most parts of the developing world. Currenttreatments do not provide a cure and are limited to only two classes ofagents (interferon and nucleoside analogues/inhibitors of the viralpolymerase); drug resistance, low efficacy, and tolerability issueslimit their impact. The low cure rates of HBV are attributed at least inpart to the presence and persistence of covalently closed circular DNA(cccDNA) in the nucleus of infected hepatocytes. However, persistentsuppression of HBV DNA slows liver disease progression and helps toprevent HCC. Current therapy goals for HBV-infected patients aredirected to reducing serum HBV DNA to low or undetectable levels, and toultimately reducing or preventing the development of cirrhosis and HCC.

The HBV is an enveloped, partially double-stranded DNA (dsDNA) virus ofthe hepadnavirus family (Hepadnaviridae). HBV capsid or core protein(CP) plays essential roles in HBV replication. The predominantbiological function of capsid protein is to act as a structural proteinto encapsidate pre-genomic RNA and form immature capsid particles, whichspontaneously self-assemble from many copies of core dimers in thecytoplasm. Capsid protein also regulates viral DNA synthesis throughdifferent phosphorylation status of its C-terminal phosphorylationsites. Also, capsid protein might facilitate the nuclear translocationof viral relaxed circular genome by means of the nuclear localizationsignals located in the Arginine-rich domain of the C-terminal region ofcapsid protein. In the nucleus, as a component of viral cccDNAminichromosome, capsid protein could play a structural and regulatoryrole in the functionality of cccDNA minichromosomes. Capsid protein alsointeracts with viral large envelope protein in endoplasmic reticulum(ER) and triggers the release of intact viral particles fromhepatocytes.

Capsid related anti-HBV inhibitors have been reported. For example,phenylpropen-amide derivatives, including compounds named AT-61 andAT-130 (Feld J. et al. Antiviral Res. 2007, 76, 168), and a class ofthiazolidin-4-ones from Valeant (WO2006/033995), have been shown toinhibit pregenomic RNA (pgRNA) packaging. Heteroaryldihydropyrimidinesor HAPs were discovered in a tissue culture-based screening (Weber etal., Antiviral Res. 2002, 54, 69). These HAP analogs act as syntheticallosteric activators and are able to induce aberrant capsid formationthat leads to degradation of the core protein. A subclass ofsulphamoylarylamides shows activity against HBV (WO2013/006394,WO2013/096744, WO2014/184365, and WO2017/136403. It was also shown thatthe small molecule bis-ANS acts as a molecular ‘wedge’ and interfereswith normal capsid-protein geometry and capsid formation (Zlotnick A. etal. J. Virol. 2002, 4848).

There is a need in the art for novel therapeutic agents that treat,ameliorate or prevent HBV infection. Administration of these therapeuticagents to an HBV infected patient, either as monotherapy or incombination with other HBV treatments or ancillary treatments, will leadto significantly improved prognosis, diminished progression of thedisease, and enhanced seroconversion rates.

SUMMARY OF THE INVENTION

The present invention relates to novel antiviral compounds,pharmaceutical compositions comprising such compounds, as well asmethods to treat or prevent viral (particularly HBV) infection in asubject in need of such therapy with said compounds. Compounds of thepresent invention inhibit the protein(s) encoded by hepatitis B virus(HBV) or interfere with the life cycle of HBV and are also useful asantiviral agents. In addition, the present invention includes theprocess for the preparation of the said compounds.

In its principal aspect, the present invention provides a compound ofFormula (I):X-A-Y-L-R  (I)or a pharmaceutically acceptable salt thereof, wherein:

X and Y are each independently selected from optionally substituted arylor optionally substituted heteroaryl; in one embodiment one of X and Yis optionally substituted phenyl; in another embodiment, both X and Yare optionally substituted phenyl;

A is selected from the group consisting of —NHC(O)—,

preferably A is —NHC(O)—;

L is S(O)₂, S(O), S or O; and

R is connected to L via a carbon atom and is independently selected fromthe group consisting of optionally substituted —C₁-C₁₀ alkyl, optionallysubstituted —C₂-C₁₀ alkenyl, optionally substituted —C₂-C₁₀ alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted —C₃-C₁₂ cycloalkyl, optionally substituted—C₃-C₁₂ cycloalkenyl, optionally substituted 3- to 12-memberedheterocyclic; in one embodiment, R is optionally substituted —C₅-C₁₂cycloalkyl or optionally substituted 5- to 12-membered heterocyclic,each optionally substituted with one or more of the following: fusedrings, one or more spiro rings or one or more bridging ring moieties. Inanother embodiment, R is optionally substituted C₃-C₁₂cycloalkyl-C₁-C₆-alkyl-, optionally substituted C₃-C₁₂cycloalkenyl-C₁-C₆-alkyl-, or optionally substituted 3- to 12-memberedheterocyclic-C₁-C₆-alkyl-.

Each preferred group stated above can be taken in combination with one,any or all other preferred groups.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention is a compound of Formula (I)described above, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention relates to compounds ofFormula (I), and their pharmaceutically acceptable salts thereof,wherein X is optionally substituted phenyl. In certain embodiments, X isphenyl substituted with one or more substituents, such as 1, 2, 3, 4 or5 substituents. Preferably the substituents are independently selectedfrom halogen, CN, optionally substituted —C₁-C₃ alkoxy, optionallysubstituted —C₁-C₃ alkyl, and optionally substituted —C₃-C₆ cycloalkyl.In certain embodiments, X is phenyl substituted with one or moresubstituents independently selected from fluoro, chloro, bromo, methyl,difluoromethyl, trifluoromethyl, CN and cyclopropyl. In certainembodiments, X is selected from the groups below:

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein X isoptionally substituted monocyclic heteroaryl. In certain embodiments,the present invention relates to compounds of Formula (I) or, andpharmaceutically acceptable salts thereof, wherein X is optionallysubstituted thiophenyl, optionally substituted thiazolyl, optionallysubstituted pyridyl, or optionally substituted pyrimidinyl. In certainembodiments, the present invention relates to compounds of Formula (I)or, and pharmaceutically acceptable salts thereof, wherein X isoptionally substituted pyrimidinyl, optionally substituted pyridazyl, oroptionally substituted pyrazyl as shown below:

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein X isoptionally substituted bicyclic heteroaryl. In certain embodiments, thepresent invention relates to compounds of Formula (I), andpharmaceutically acceptable salts thereof, wherein X is optionallysubstituted 5/6 bicyclic heteroaryl and is connected to A through eithera carbon or nitrogen atom, preferably a carbon atom, of the 6-memberedring of said 5/6 bicyclic heteroaryl. In certain embodiments, thepresent invention relates to compounds of Formula (I), andpharmaceutically acceptable salts thereof, wherein X is optionallysubstituted benzimidazolyl, benzothiazolyl, benzoxazolyl, indazolyl,quinolyl, isoquinolyl or quinazolyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Y isoptionally substituted phenyl. In certain embodiments, the presentinvention relates to compounds of Formula (I), and pharmaceuticallyacceptable salts thereof, wherein Y is phenyl substituted with halogen,CN, optionally substituted —C₁-C₆ alkoxy, optionally substituted —C₁-C₆alkyl, optionally substituted —C₁-C₆ alkenyl, optionally substituted—C₃-C₆ cycloalkyl, optionally substituted aryl and optionallysubstituted heteroaryl. In certain embodiments, the present inventionrelates to compounds of Formula (I), and pharmaceutically acceptablesalts thereof, wherein Y is optionally substituted 1,3-phenylene, forexample

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Y isoptionally substituted 1, 3-phenylene, for example

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Y isoptionally substituted 2,4-pyrrolylene, for example

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Y isoptionally substituted monocyclic heteroaryl. In certain embodiments,the present invention relates to compounds of Formula (I) andpharmaceutically acceptable salts thereof, wherein Y is optionallysubstituted thiophenyl, optionally substituted thiazolyl, optionallysubstituted pyrrolyl, optionally substituted pyrazolyl, optionallysubstituted imidazolyl, optionally substituted pyridyl, or optionallysubstituted pyrimidinyl. In certain embodiments, the present inventionrelates to compounds of Formula (I) and pharmaceutically acceptablesalts thereof, wherein Y is pyrrolyl optionally substituted withhalogen, CN and optionally substituted —C₁-C₃ alkyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Y isoptionally substituted bicyclic heteroaryl. In certain embodiments, thepresent invention relates to compounds of Formula (I), andpharmaceutically acceptable salts thereof, wherein Y is optionallysubstituted 5/6 bicyclic heteroaryl and is connected to A through eithera carbon or nitrogen atom of the 5-membered ring of said 5/6 bicyclicheteroaryl. In certain embodiments, the present invention relates tocompounds of Formula (I), and pharmaceutically acceptable salts thereof,wherein Y is optionally substituted benzimidazolyl, benzothiazolyl,benzoxazolyl, indazolyl, quinolyl, isoquinolyl or quinazolyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Xand Y are each independently optionally substituted monocyclicheteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein X isoptionally substituted phenyl and Y is optionally substituted monocyclicheteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein X isoptionally substituted monocyclic heteroaryl and Y is optionallysubstituted phenyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Xand Y are each independently phenyl or monocyclic heteroaryl, eachoptionally substituted with 1- to 3-substituents selected from the groupconsisting of halogen, CN, optionally substituted methyl, optionallysubstituted methoxy, and optionally substituted cyclopropyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Xand Y are each independently selected from the group consisting ofoptionally substituted phenyl, optionally substituted thiophenyl,optionally substituted pyridyl, and optionally substituted pyrimidyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein Xand Y are each independently optionally substituted phenyl. In certainembodiments, the present invention relates to compounds of Formula (I),and pharmaceutically acceptable salts thereof, wherein X is optionallysubstituted phenyl and Y is optionally substituted pyrrolyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein A is—NHC(O)—.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein A is—NHC(O)—,

and the said nitrogen of —NHC(O)—,

is connected to X.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein A is—NHC(O)—,

and the said nitrogen of —NHC(O)—,

is connected to Y.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein L isS(O)₂.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein L isS(O).

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein L isS.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein L isO.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R isoptionally substituted —C₁-C₁₀ alkyl, optionally substituted —C₂-C₁₀alkenyl, or optionally substituted —C₂-C₁₀ alkynyl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R isoptionally substituted aryl or optionally substituted heteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R isoptionally substituted —C₃-C₁₂ cycloalkyl or optionally substituted 3-to 12-membered heterocyclic.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R isoptionally substituted C₃-C₁₂ cycloalkyl-C₁-C₆-alkyl-, optionallysubstituted C₃-C₁₂ cycloalkenyl-C₁-C₆-alkyl-, or optionally substituted3- to 12-membered heterocyclic-C₁-C₆-alkyl-.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R isoptionally substituted —C₅-C₁₂ cycloalkyl or optionally substituted 5-to 12-membered heterocyclic, each optionally substituted with one ormore fused rings.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R isoptionally substituted —C₅-C₁₂ cycloalkyl or optionally substituted 5-to 12-membered heterocyclic, each optionally substituted with one ormore spiro rings.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R isoptionally substituted —C₅-C₁₂ cycloalkyl or optionally substituted 5-to 12-membered, each optionally comprising a bridging moiety.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R is—C(R₁₀)₃,

wherein n at each occurrence is independently selected from 0, 1, 2, or3; T at each occurrence is independently selected from C(R₁₀) and N; Eat each occurrence is independently selected from —C(R₁₀)₂—, —N(R₁₀)—,O, S, S(O), and S(O)₂; wherein R₁₀ at each occurrence is independentlyselected from the group consisting of hydrogen, halo, —CN, —NO₂,optionally substituted —C₁-C₆ alkyl, optionally substituted —C₂-C₈alkenyl, optionally substituted —C₂-C₈ alkynyl, optionally substituted—C₃-C₈ cycloalkyl, optionally substituted 3- to 8-membered heterocyclic,optionally substituted aryl, optionally substituted heteroaryl, and-L₁-R₁; wherein L₁ is —O—, —S—, —NR₁—, —C(O)—, —C(O)O—, —OC(O)—,—C(O)N(R₁)—, —N(R₁)C(O)—, —OC(O)N(R₁)—, —N(R₁)C(O)O—, —N(R₁)C(O)N(R₁)—,—S(O)—, —S(O)₂—, —S(O)₂N(R₁)—, —N(R₁)S(O)₂—; R₁ at each occurrence isindependently selected from the group consisting of hydrogen, optionallysubstituted —C₁-C₆ alkyl, optionally substituted —C₂-C₈ alkenyl,optionally substituted —C₂-C₈ alkynyl, optionally substituted —C₃-C₈cycloalkyl, optionally substituted 3- to 8-membered heterocyclic,optionally substituted aryl, and optionally substituted heteroaryl.

In certain embodiments, each R₁₀ is independently selected fromhydrogen, halo, hydroxy, protected hydroxy, —CN, —NO₂, amino, protectedamino, optionally substituted —C₁-C₆ alkyl, optionally substituted—C₁-C₆ alkoxy, optionally substituted aryl, optionally substitutedheteroaryl and —O-(hydroxy prodrug group). In certain embodiments, thehydroxy prodrug group is phosphate or sulfamate. In certain embodiments,the said hydroxy prodrug group is an acyl group derived from an aminoacid, preferably an α-amino acid.

In certain embodiments, each R₁₀ is independently —C₁-C₆ alkyloptionally substituted with one or more substitutents selected from thegroup consisting of halo, hydroxy, protected hydroxy, amino, protectedamino, and optionally substituted heteroaryl.

In certain embodiments, two adjacent R₁₀ groups are taken together withthe carbon or nitrogen atoms to which they are attached to form anolefinic or iminic double-bond or a fused ring. In certain embodiments,two geminal R₁₀ groups together form an oxo, an optionally substitutedolefin, an optionally substituted oxime, or a spiro ring. In certainembodiments, two remote R₁₀ groups are taken together with the atoms towhich they are attached and any intervening atoms to form a bridgingmoiety.

In certain embodiments, the present invention relates to compounds ofFormula (I), and pharmaceutically acceptable salts thereof, wherein R isoptionally substituted —(CH₂)₀₋₄—C(R₁₀)₃,

wherein n, E, T and R₁₀ are previously defined; v is selected from 1, 2,3 or 4. In certain embodiments, each R₁₀ is independently selected fromhydrogen, halo, hydroxy, protected hydroxy, —CN, —NO₂, amino, protectedamino, optionally substituted —C₁-C₆ alkyl, optionally substituted—C₁-C₆ alkoxy, optionally substituted aryl, optionally substitutedheteroaryl and —O— (hydroxy prodrug group). In certain embodiments, thehydroxy prodrug group is phosphate or sulfamate. In certain embodiments,the said hydroxy prodrug group is an acyl group derived from an aminoacid, preferably an α-amino acid. In certain embodiments, each R₁₀ isindependently —C₁-C₆ alkyl optionally substituted with one or moresubstitutents selected from the group consisting of halo, hydroxy,protected hydroxy, amino, protected amino, and optionally substitutedheteroaryl. In certain embodiments, two adjacent R₁₀ groups are takentogether with the carbon or nitrogen atoms to which they are attached toform an olefinic double-bond, an iminic double bond or a fusedcarbocyclic or heterocyclic ring. In certain embodiments, two geminalR₁₀ groups together form an oxo, an optionally substituted olefin, anoptionally substituted oxime, or a spiro ring. In certain embodiments,two remote R₁₀ groups are taken together with the atoms to which theyare connected and any intervening atoms to form a bridging moiety.

In certain embodiments, R is selected from the groups below, and isoptionally substituted:

In certain embodiments, R is selected from the groups set forth below,and is optionally substituted:

In another embodiment, the compound of Formula (I) is represented byFormula (Ia), (Ib), (Ic), or (Id) or a pharmaceutically acceptable saltthereof:

wherein X, A, Y, and R are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), or (IIh), or apharmaceutically acceptable salt thereof:

wherein X, Y, and R are as previously defined.

In certain embodiments, the present invention relates to compounds ofFormula (I) represented by Formula (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), or (IIh), or pharmaceutically acceptable salts thereof,wherein X and Y are each independently optionally substituted phenyl oroptionally substituted monocyclic heteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (I) represented by Formula (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), or (IIh), or pharmaceutically acceptable salts thereof, Xand Y are each independently optionally substituted phenyl.

In certain embodiments, the present invention relates to compounds ofFormula (I) represented by Formula (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), or (IIh), or pharmaceutically acceptable salts thereof,wherein X is optionally substituted phenyl and Y is optionallysubstituted 5-membered heteroaryl.

In certain embodiments, the present invention relates to compounds ofFormula (I) represented by Formula (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), or (IIh), or pharmaceutically acceptable salts thereof,wherein X is optionally substituted 5-membered heteroaryl and Y isoptionally substituted phenyl.

In certain embodiments, the present invention relates to compounds ofFormula (I) represented by Formula (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), or (IIh), or pharmaceutically acceptable salts thereof,wherein X is optionally substituted phenyl and Y is optionallysubstituted pyrrolyl.

In certain embodiments, the present invention relates to compounds ofFormula (I) represented by Formula (IIa), (IIb), (IIc), (IId), (IIe),(IIf), (IIg), or (IIh), or pharmaceutically acceptable salts thereof,wherein X and Y are each independently optionally substituted phenyl,optionally substituted naphthyl, optionally substituted pyridyl,optionally substituted pyrimidinyl, optionally substituted thiophenyl,optionally substituted pyrrolyl, optionally substituted thiazolyl,optionally substituted thiadiazolyl, optionally substituted oxazolyl,optionally substituted isoxazolyl, optionally substituted oxadiazolyl,optionally substituted imidiazolyl, optionally substituted pyrazolyl,optionally substituted triazolyl, or optionally substituted quinolinyl.

In another embodiment, the compound of Formula (I) is represented byFormula (IIIa), (IIIb), (IIIc), or (IIId), or a pharmaceuticallyacceptable salt thereof:

wherein m at each occurrence is independently 0, 1, 2, 3 or 4; R₁₀ ateach occurrence is independently selected from the group consisting ofhydroxy, protected hydroxy, halogen, —CN, —NO₂, optionally substitutedamino, N₃, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted —C₁-C₆ alkyl, optionally substituted—C₂-C₈ alkenyl, optionally substituted —C₂-C₈ alkynyl, optionallysubstituted —C₃-C₈ cycloalkyl, optionally substituted 3- to 8-memberedheterocyclic, optionally substituted —C₁-C₆ alkoxy, —C(O)₂—C₁-C₆ alkyl,—C(O)NH—C₁-C₆ alkyl, and —C(O)—C₁-C₆ alkyl; and R is as previouslydefined.

In another embodiment, the compound of Formula (I) is represented byFormula (IIIa-1), (IIIb-1), (IIIc-1), or (IIId-1), or a pharmaceuticallyacceptable salt thereof:

wherein X, R, R₁₄, and m are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (IIIa-2), (IIIb-2), (IIIc-2), or (IIId-2), or a pharmaceuticallyacceptable salt thereof:

wherein Y, R, R₁₄, and m are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (IVa), (IVb), (IVc), (IVd), or (IVe) or a pharmaceuticallyacceptable salt thereof:

wherein E, T, m, n, R₁₀, and R₁₄ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (Va), (Vb), (Vc), (Vd), or (Ve), or a pharmaceuticallyacceptable salt thereof:

wherein m1 at each occurrence is independently 1, 2, or 3; m2 at eachoccurrence is independently 0, 1, or 2; m3 at each occurrence isindependently 0, 1, 2, or 3; R₂₁ at each occurrence is independentlyselected from the group consisting of halogen, CN, optionallysubstituted —C₁-C₆ alkyl, optionally substituted —C₁-C₆ alkoxy, andoptionally substituted C₃-C₈ cycloalkyl; R₂₂ at each occurrence isindependently selected from the group consisting of halogen, CN,optionally substituted —C₁-C₆ alkyl, optionally substituted —C₁-C₆alkoxy, optionally substituted aryl, and optionally substitutedheteroaryl; E, n, and R₁₀ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (Vf), (Vg), (Vh), or (Vj), or a pharmaceutically acceptable saltthereof:

wherein m4 at each occurrence is independently 0, 1, or 2; R₃₀ ishydrogen, optionally substituted —C₁-C₆ alkyl, a hydroxy protectinggroup or a hydroxy prodrug group; m1, m2, n, E, R₁₀, R₂₁, and R₂₂ are aspreviously defined. In certain embodiments, R₃₀ is phosphate orsulfamate. In certain embodiments, R₃₀ is an acyl group derived from anamino acid, preferably an α-amino acid.

In another embodiment, the compound of Formula (I) is represented byFormula (VIa), (VIb), (VIc), (VId), (VIe), or (VIf), or apharmaceutically acceptable salt thereof:

wherein m1 at each occurrence is independently 1, 2, or 3; m2 at eachoccurrence is independently 1, or 2; n, R₂₁, R₂₂, and R₃₀ are aspreviously defined. In certain embodiments, R₃₀ is phosphate orsulfamate. In certain embodiments, R₃₀ is an acyl group derived from anamino acid, preferably an α-amino acid.

In another embodiment, the compound of Formula (I) is represented byFormula (VIa), (VIb), (VIc), (VId), (VIe), or (VIf), or apharmaceutically acceptable salt thereof, wherein m1 at each occurrenceis independently 2 or 3; m2 at each occurrence is 1; n at eachoccurrence is independently 0, 1, or 2; R₂₁ is halogen, CN, optionallysubstituted methyl, optionally substituted methoxy, and optionallysubstituted cyclopropyl; R₂₂ is halogen, CN, optionally substitutedmethyl, and optionally substituted methoxy; R₃₀ is acyl group derivedfrom an amino acid. In certain embodiments, R₃₀ is acyl group derivedfrom an α-amino acid having an aliphatic side-chain. In certainembodiments, R₃₀ is acyl group derived from alaline or valine.

In another embodiment, the compound of Formula (I) is represented byFormula (VIIa), (VIIb), (VIIc), (VIId), or (VIIe), or a pharmaceuticallyacceptable salt thereof:

wherein m1, m3, n, E, R₁₀, R₂₁, and R₂₂ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (VIIa-1), (VIIb-1), (VIIc-1), (VIId-1), or (VIIe-1), or apharmaceutically acceptable salt thereof:

wherein R₂₃ at each occurrence is independently selected from the groupconsisting of hydrogen, halogen, CN, optionally substituted —C₁-C₆alkyl, optionally substituted —C₁-C₆ alkoxy, and optionally substitutedC₃-C₈ cycloalkyl; m3, n, E, R₁₀, R₂₁, and R₂₂ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (VIIa-2), (VIIb-2), (VIIc-2), or (VIId-2), or a pharmaceuticallyacceptable salt thereof:

wherein m4, n, E, R₁₀, R₂₁, R₂₂, R₂₃, and R₃₀ are as previously defined.In certain embodiments, R₃₀ is hydrogen. In certain embodiments, R₃₀ isacyl group derived from an amino acid, preferably an α-amino acid.

In another embodiment, the compound of Formula (I) is represented byFormula (VIIa-2), (VIIb-2), (VIIc-2), or (VIId-2), or a pharmaceuticallyacceptable salt thereof, wherein n at each occurrence is independently0, 1, or 2; R₂₁ at each occurrence is independently halogen, CN,optionally substituted methyl, optionally substituted methoxy, oroptionally substituted cyclopropyl; R₂₂ is halogen, CN, optionallysubstituted methyl, or optionally substituted methoxy; R₂₃ is hydrogenor halogen; R₁₀ is hydrogen, halogen, hydroxyl, or optionallysubstituted C₁-C₆ alkyl; R₃₀ is hydrogen or acyl group derived from anamino acid. In certain embodiments, R₂₁ at each occurrence is fluorine.In certain embodiments, R₂₂ is fluorine or chlorine. In certainembodiments, R₁₀ is hydrogen, halogen, hydroxyl, C₁-C₆ alkyl optionallysubstituted with one or more groups selected from halogen, hydroxy andoptionally substituted C₁-C₆ alkoxy. In certain embodiments, R₂₃ ishydrogen or fluorine. In certain embodiments, R₃₀ is an acyl groupderived from alanine or valine.

In another embodiment, the compound of Formula (I) is represented byFormula (VIIIa), (VIIIb), (VIIIc), or (VIIId), or a pharmaceuticallyacceptable salt thereof:

wherein R₁₁ at each occurrence is independently selected from the groupconsisting of hydrogen, halogen, hydroxy, protected hydroxy, —CN, amino,protected amino, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted —C₁-C₆ alkyl, optionally substituted—C₂-C₈ alkenyl, optionally substituted —C₂-C₈ alkynyl, optionallysubstituted —C₃-C₈ cycloalkyl, optionally substituted 3- to 8-memberedheterocyclic, optionally substituted —C₁-C₆ alkoxy, optionallysubstituted —NH—C₁-C₆ alkyl, optionally substituted —N(C₁-C₆ alkyl)₂,—CO₂H, optionally substituted —C(O)₂—C₁-C₆ alkyl, optionally substituted—C(O)NH—C₁-C₆ alkyl, and optionally substituted —C(O)—C₁-C₆ alkyl; m, n,E, T, R₁₀ and R₁₄ are as previously defined. In certain embodiments, thepreferred R₁₁ groups include hydrogen, halogen, hydroxy, protectedhydroxy, protected amino, optionally substituted aryl, optionallysubstituted heteroaryl, —CO₂H, optionally substituted —C₁-C₆ alkyl,optionally substituted NHC(O)₂—C₁-C₆ alkyl, and optionally substituted—C₁-C₆ alkoxy. In certain embodiments, R₁₁ is optionally substituted—C₁-C₆ alkyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted —C₁-C₆ alkoxy.

In another embodiment, the compound of Formula (I) is represented byFormula (VIIIa-1), (VIIIb-1), (VIIIc-1), or (VIIId-1), or apharmaceutically acceptable salt thereof:

wherein m, n, E, R₁₀, R₁₁, and R₁₄ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (IXa), (IXb), (IXc), or (IXd), or a pharmaceutically acceptablesalt thereof:

wherein m4, n, R₁₀, R₂₁, R₂₂, R₂₃, and R₃₀ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (Xa), (Xb), (Xc), or (Xd), or a pharmaceutically acceptable saltthereof:

wherein m4, n, R₁₀, R₂₁, R₂₂, R₂₃, and R₃₀ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (XIa), (XIb), (XIc), or (XId), or a pharmaceutically acceptablesalt thereof:

wherein m4, n, R₁₀, R₂₁, R₂₂, R₂₃, and R₃₀ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (XIIa), (XIIb), (XIIc), or (XIId), or a pharmaceuticallyacceptable salt thereof:

wherein R₃₁ at each occurrence is independently selected from the groupconsisting of hydrogen, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted —C₁-C₆ alkyl, optionallysubstituted —C₂-C₈ alkenyl, optionally substituted —C₂-C₈ alkynyl,optionally substituted —C₃-C₈ cycloalkyl, and optionally substituted 3-to 8-membered heterocyclic; m1, m2, m4, n, R₁₀, R₁₁, R₁₂, R₂₂, and R₃₀are as previously defined. In certain embodiments, R₃₁ is —C₁-C₆ alkyloptionally substituted with one or more groups selected from halogen,hydroxy, optionally substituted C₁-C₆ alkoxy, amino, optionallysubstituted —NH—C₁-C₆ alkyl, optionally substituted —N(C₁-C₆ alkyl)₂,optionally substituted —CO₂—C₁-C₆ alkyl, optionally substituted—C(O)NH—C₁-C₆ alkyl, optionally substituted —NHC(O)—C₁-C₆ alkyl,optionally substituted —C(O)—C₁-C₆ alkyl, and optionally substituted—NHS(O)₂—C₁-C₆ alkyl.

In another embodiment, the compound of Formula (I) is represented byFormula (XIIIa), (XIIIb), (XIIIc), or (XIIId), or a pharmaceuticallyacceptable salt thereof:

wherein R₃₂ at each occurrence is independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted —C(O)—C₁-C₆ alkyl, optionally substituted —C(O)—C₂-C₈alkenyl, optionally substituted —C(O)—C₂-C₈ alkynyl, optionallysubstituted —C(O)—C₃-C₈ cycloalkyl, optionally substituted —C(O)-aryl,optionally substituted —C(O)-(3- to 8-membered heterocyclic), optionallysubstituted —C(O)—C₁-C₆ alkyl, optionally substituted —CO₂—C₁-C₆ alkyl,optionally substituted S(O)₂—C₁-C₆ alkyl, optionally substitutedS(O)₂—C₂-C₆ alkenyl; preferably when one R₃₂ is optionally substituted—C(O)—C₁-C₆ alkyl, optionally substituted —C(O)—C₂-C₈ alkenyl,optionally substituted —C(O)—C₂-C₈ alkynyl, optionally substituted—C(O)—C₃-C₈ cycloalkyl, optionally substituted —C(O)-aryl, optionallysubstituted —C(O)-(3- to 8-membered heterocyclic), optionallysubstituted —C(O)—C₁-C₆ alkyl, optionally substituted —CO₂—C₁-C₆ alkyl,optionally substituted S(O)₂—C₁-C₆ alkyl, optionally substitutedS(O)₂—C₂-C₆ alkenyl, the other R₃₂ is hydrogen or optionally substitutedC₁-C₆ alkyl; m1, m2, m4, n, R₁₀, R₁₁, R₂₁, R₂₂, and R₃₀ are aspreviously defined. In certain embodiment, two R₃₂ groups are takentogether with the nitrogen atom to which they are attached to form a 3-to 8-membered heterocyclic ring.

In another embodiment, the compound of Formula (I) is represented byFormula (XIVa), (XIVb), (XIVc), or (XIVd), or a pharmaceuticallyacceptable salt thereof:

wherein R₃₃ at each occurrence is independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted —C₂-C₈ alkenyl, optionally substituted —C₂-C₈ alkynyl,optionally substituted —C₃-C₈ cycloalkyl, optionally substituted 3- to8-membered heterocyclic, optionally substituted —C₁-C₆ alkoxy,optionally substituted —NH—C₁-C₆ alkyl, optionally substituted —N(C₁-C₆alkyl)₂, optionally substituted —NH—C₁-C₆ alkenyl, optionallysubstituted —NH-(3- to 8-membered heterocyclic); m1, m2, m4, n, R₁₀,R₁₁, R₂₁, R₂₂, and R₃₀ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (XVa), (XVb), (XVc), or (XVd), or a pharmaceutically acceptablesalt thereof:

wherein R₃₄ at each occurrence is independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted —C₂-C₈ alkenyl, optionally substituted —C₂-C₈ alkynyl,optionally substituted —C₃-C₈ cycloalkyl, and optionally substituted 3-to 8-membered heterocyclic; m1, m2, m4, n, R₁₀, R₁₁, R₂₁, R₂₂, R₃₀ andR₃₁ are as previously defined.

In another embodiment, the compound of Formula (I) is represented byFormula (XVI), or a pharmaceutically acceptable salt thereof:

wherein R₂₁, R₂₁′ and R₂₁″ are independently selected from hydrogen,fluorine, methyl, difluoromethyl, and trifluoromethyl; and R₃₅ is—[CH(R₃₆)]_(p)—C(R₃₇)(R₃₈)OH or —CH₂—O—CH₂—[CH(R₃₆)]_(p)C(R₃₇)(R₃₈)OH,wherein p is 0 or 1; R₃₆ is hydrogen, methyl or hydroxyl; and R₃₇ andR₃₈ are independently hydrogen or methyl. Preferably, at least two ofR₂₁, R₂₁′ and R₂₁″ are not hydrogen. More preferably, (i) none of R₂₁,R₂₁′ and R₂₁″ is hydrogen; or (ii) R₂₁ is hydrogen and R₂₁′ and R₂₁″ arenot hydrogen. In preferred embodiments, at least two of R₂₁ R_(21′) andR_(21″) are fluorine. In other embodiments, each of R₂₁, R₂₁′ and R₂₁″is fluorine.

In another embodiment, the compound of Formula (I) is represented byFormula (XVII), or a pharmaceutically acceptable salt thereof:

wherein R₂₁, R₂₁′ and R₂₁″ are independently selected from hydrogen,fluorine, methyl, difluoromethyl, and trifluoromethyl; R₃₉ is hydrogenor hydroxyl; and R₄₀ is —[C(R₄₁)(R₄₂)]_(q)—R₄₃, wherein q is 0, 1 or 2;R₄₁ and R₄₂ are each independently hydrogen, methyl, or hydroxyl; oralternatively, R₄₁ and R₄₂ can be taken together to form an oxo; and R₄₃is hydrogen, hydroxyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₆ cycloalkyl, optionally substituted 3- to 12-memberedheterocyclic, optionally substituted aryl or optionally substitutedheteroaryl. Preferably, at least two of R₂₁, R₂₁′ and R₂₁″ are nothydrogen. More preferably, (i) none of R₂₁, R₂₁′ and R₂₁″ is hydrogen;or (ii) R₂₁ is hydrogen and R₂₁′ and R₂₁″ are not hydrogen. In preferredembodiments, at least two of R₂₁ R_(21′) and R_(21″) are fluorine. Inother embodiments, each of R₂₁, R₂₁′ and R₂₁″ is fluorine. Preferably,R₃₉ is hydroxyl; q is 1 or 2; R₄₁ and R₄₂ are each independentlyhydrogen or hydroxyl; and R₄₃ is optionally substituted C₁-C₆ alkyl,optionally substituted C₃-C₆ cycloalkyl, optionally substituted 3- to12-membered heterocyclic, optionally substituted aryl or optionallysubstituted heteroaryl. More preferably, R₃₉ is hydroxyl; q is 1 or 2;R₄₁ is hydrogen; R₄₂ is hydroxyl; and R₄₃ is optionally substitutedC₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl, optionallysubstituted 3- to 12-membered heterocyclic, or optionally substitutedheteroaryl. In preferred embodiments, R₃₉ is hydrogen or hydroxyl; q is1 or 2; R₄₁ is hydrogen or methyl; R₄₂ is hydroxyl; and R₄₃ isoptionally substituted C₁-C₆ alkyl or optionally substituted C₃-C₆cycloalkyl. In other embodiments, R₃₉ is hydrogen or hydroxyl; q is 1 or2; R₄₁ is hydrogen or methyl; R₄₂ is hydroxyl; and R₄₃ is optionallysubstituted 3- to 12-membered heterocyclic or optionally substitutedheteroaryl. In preferred embodiments, R₄₃ is methyl, ethyl, propyl,isopropyl, cyclopropyl, cyclobutyl, pyridyl, pyrimidinyl, oxazolyl,thiazolyl, oxazolyl, or isoxazolyl.

It will be appreciated that the description of the present inventionherein should be construed in congruity with the laws and principles ofchemical bonding. In some instances, it may be necessary to remove ahydrogen atom in order to accommodate a substituent at any givenlocation.

It will be yet appreciated that the compounds of the present inventionmay contain one or more asymmetric carbon atoms and may exist inracemic, diastereoisomeric, and optically active forms. It will still beappreciated that certain compounds of the present invention may exist indifferent tautomeric forms. All tautomers are contemplated to be withinthe scope of the present invention.

In one aspect, the compounds of the invention are useful in HBVtreatment by disrupting, accelerating, reducing, delaying and/orinhibiting normal viral core protein functions including, but notlimited to, direct or indirect interaction with viral relaxed circular(rc) DNA, cccDNA, or reverse transcriptase, direct or indirectinteraction with host proteins such as histones or host partners such askinase, capsid assembly and/or disassembly of immature or matureparticles, thereby inducing aberrant capsid morphology and leading toantiviral effects such as disruption of virion assembly and/ordisassembly, virion maturation, and/or virus egress. In one embodiment,a disruptor of capsid assembly interacts with mature or immature viralcapsid to perturb the stability of the capsid, thus affecting assemblyand/or disassembly. In another embodiment, a disruptor of capsidassembly perturbs protein folding and/or salt bridges required forstability, function and/or normal morphology of the viral capsid,thereby disrupting and/or accelerating capsid assembly and/ordisassembly. In yet another embodiment, the compounds of the inventionbind capsid and alter metabolism of cellular polyproteins andprecursors, leading to abnormal accumulation of protein monomers and/oroligomers and/or abnormal particles, which causes cellular toxicity anddeath of infected cells. In another embodiment, the compounds of theinvention cause failure of the formation of capsid of optimal stability,affecting efficient uncoating and/or disassembly of viruses (e.g.,during infectivity).

In one embodiment, the compounds of the invention disrupt and/oraccelerate capsid assembly and/or disassembly when the capsid protein isimmature. In another embodiment, the compounds of the invention disruptand/or accelerate capsid assembly and/or disassembly when the capsidprotein is mature. In yet another embodiment, the compounds of theinvention disrupt and/or accelerate capsid assembly and/or disassemblyduring vial infectivity. In yet another embodiment, the disruptionand/or acceleration of capsid assembly and/or disassembly attenuates HBVviral infectivity and/or reduces viral load. In yet another embodiment,disruption, acceleration, inhibition, delay and/or reduction of capsidassembly and/or disassembly eradicates the virus from the host organism.In yet another embodiment, the compounds of the invention disrupt and/ormodulate the interaction between core protein and viral rcDNA, cccDNA orreverse transcriptase during vial infectivity. In yet anotherembodiment, the compounds of the invention disrupt and/or modulate theinteraction between core protein and host partners or proteins duringvial infectivity. In yet another embodiment, eradication of the HBV froma host advantageously obviates the need for chronic long-term therapyand/or reduces the duration of long-term therapy.

In one embodiment, the compounds described herein are suitable formonotherapy and are effective against natural or native HBV strains andagainst HBV strains resistant to currently known drugs. In anotherembodiment, the compounds described herein are suitable for use incombination therapy.

In another embodiment, the compounds of the invention can be used inmethods of modulating (e.g., inhibit, disrupt or accelerate) theactivity of HBV cccDNA. In yet another embodiment, the compounds of theinvention can be used in methods of diminishing or preventing theformation of HBV cccDNA. In another embodiment, the additionaltherapeutic agent is selected from immune modulator or immune stimulatortherapies, which includes T-cell response activator AIC649 andbiological agents belonging to the interferon class, such as interferonalpha 2a or 2b or modified interferons such as pegylated interferon,alpha 2a, alpha 2b, lamda; or STING (stimulator of interferon genes)modulator; or TLR modulators such as TLR-7 agonists, TLR-8 agonists orTLR-9 agonists; or therapeutic vaccines to stimulate an HBV-specificimmune response such as virus-like particles composed of HBcAg andHBsAg, immune complexes of HBsAg and HBsAb, or recombinant proteinscomprising HBx, HBsAg and HBcAg in the context of a yeast vector; orimmunity activator such as SB-9200 of certain cellular viral RNA sensorssuch as RIG-I, NOD2, and MDA5 protein; or RNA interence (RNAi) or smallinterfering RNA (siRNA) such as ARC-520, ARC-521, ARB-1467, and ALN-HBVRNAi; or another core protein inhibitor or modulator; or antiviralagents that block viral entry or maturation or target the HBV polymerasesuch as nucleoside or nucleotide or non-nucleos(t)ide polymeraseinhibitors, and agents of distinct or unknown mechanism including agentsthat disrupt the function of other essential viral protein(s) or hostproteins required for HBV replication or persistence such as REP 2139and RG7834. In an embodiment of the combination therapy, the reversetranscriptase inhibitor is at least one of Zidovudine, Didanosine,Zalcitabine, ddA, Stavudine, Lamivudine, Aba-cavir, Emtricitabine,Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir,valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA,cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In another embodiment of the combination therapy, the TLR-7 agonist isselected from the group consisting of SM360320(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)ad-enine), AZD 8848 (methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]aminoImethyl)phenyl]acetate), GS-9620(4-Amino-2-butoxy-8-[3-(1-pyrrolidinylmethyl)benzyl]-7,8-dihydro-6(5H)-pteridinone),and RO6864018.

In another embodiment of the combination therapy, the TLR-8 agonist isGS-9688.

In an embodiment of these combination therapies, the compound and theadditional therapeutic agent are co-formulated. In another embodiment,the compound and the additional therapeutic agent are co-administered.

In another embodiment of the combination therapy, administering thecompound of the invention allows for administering of the additionaltherapeutic agent at a lower dose or frequency as compared to theadministering of the at least one additional therapeutic agent alonethat is required to achieve similar results in prophylactically treatingan HBV infection in an individual in need thereof.

In another embodiment of the combination therapy, before administeringthe therapeutically effective amount of the compound of the invention,the individual is known to be refractory to a compound selected from thegroup consisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, andcombination thereof.

In still another embodiment of the method, administering the compound ofthe invention reduces viral load in the individual to a greater extentcompared to the administering of a compound selected from the groupconsisting of a HBV polymerase inhibitor, interferon, viral entryinhibitor, viral maturation inhibitor, distinct capsid assemblymodulator, antiviral compounds of distinct or unknown mechanism, andcombination thereof.

In another embodiment, administering of the compound of the inventioncauses a lower incidence of viral mutation and/or viral resistance thanthe administering of a compound selected from the group consisting of anHBV polymerase inhibitor, interferon, viral entry inhibitor, viralmaturation inhibitor, distinct capsid assembly modulator, antiviralcompounds of distinct or unknown mechanism, and combination thereof.

It should be understood that the compounds encompassed by the presentinvention are those that are suitably stable for use as pharmaceuticalagent.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system comprising at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system thatcomprises at least one aromatic ring. Polycyclic aryls can comprisefused rings, covalently attached rings or a combination thereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fusedrings, covalently attached rings or a combination thereof.

In accordance with the invention, aromatic groups can be substituted orunsubstituted.

The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ringsystem consisting of two rings wherein at least one ring is aromatic;and the two rings can be fused or covalently attached.

The term “alkyl” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals. “C₁-C₃ alkyl,” “C₁-C₆ alkyl,”“C₁-C₁₀ alkyl,” “C₂-C₄ alkyl,” or “C₃-C₆ alkyl,” refer to alkyl groupscontaining from one to three, one to six, one to ten carbon atoms, 2 to4 and 3 to 6 carbon atoms respectively. Examples of C₁-C₈ alkyl radicalsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.

The term “alkenyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon double bond bythe removal of a single hydrogen atom. “C₂-C₁₀ alkenyl,” “C₂-C₈alkenyl,” “C₂-C₄ alkenyl,” or “C₃-C₆ alkenyl,” refer to alkenyl groupscontaining from two to ten, two to eight, two to four or three to sixcarbon atoms respectively. Alkenyl groups include, but are not limitedto, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl,heptenyl, octenyl, and the like.

The term “alkynyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon triple bond bythe removal of a single hydrogen atom. “C₂-C₁₀ alkynyl,” “C₂-C₈alkynyl,” “C₂-C₄ alkynyl,” or “C₃-C₆ alkynyl,” refer to alkynyl groupscontaining from two to ten, two to eight, two to four or three to sixcarbon atoms respectively. Representative alkynyl groups include, butare not limited to, for example, ethynyl, 1-propynyl, 1-butynyl,heptynyl, octynyl, and the like.

The term “cycloalkyl”, as used herein, refers to a monocyclic orpolycyclic saturated carbocyclic ring or a bi- or tri-cyclic groupfused, bridged or spiro system, and the carbon atoms may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic,iminic or oximic double bond. Preferred cycloalkyl groups include C₃-C₁₂cycloalkyl, C₃-C₆ cycloalkyl, C₃-C₈ cycloalkyl and C₄-C₇ cycloalkyl.Examples of C₃-C₁₂ cycloalkyl include, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl,4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl,spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, andthe like.

The term “cycloalkenyl”, as used herein, refers to monocyclic orpolycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridgedor spiro system having at least one carbon-carbon double bond and thecarbon atoms may be optionally oxo-substituted or optionally substitutedwith exocyclic olefinic, iminic or oximic double bond. Preferredcycloalkenyl groups include C₃-C₁₂ cycloalkenyl, C₃-C₈ cycloalkenyl orC₅-C₇ cycloalkenyl groups. Examples of C₃-C₁₂ cycloalkenyl include, butnot limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl,bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl,bicyclo[4.2.1]non-3-en-9-yl, and the like.

As used herein, the term “arylalkyl” means a functional group wherein analkylene chain is attached to an aryl group, e.g., —CH₂CH₂-phenyl. Theterm “substituted arylalkyl” means an arylalkyl functional group inwhich the aryl group is substituted. Similarly, the term“heteroarylalkyl” means a functional group wherein an alkylene chain isattached to a heteroaryl group. The tem “substituted heteroarylalkyl”means a heteroarylalkyl functional group in which the heteroaryl groupis substituted.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms connected to the rest of the moleculevia an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy,2-propoxy (isopropoxy) and the higher homologs and isomers. Preferredalkoxy are (C₁-C₃) alkoxy.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclic and cycloalkenyl moiety described herein can also be analiphatic group or an alicyclic group.

An “aliphatic” group is a non-aromatic moiety comprised of anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contains one or more units ofunsaturation, e.g., double and/or triple bonds. Examples of aliphaticgroups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH,NH, NH₂, C(O), S(O)₂, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH₂, S(O)₂NH,S(O)₂NH₂, NHC(O)NH₂, NHC(O)C(O)NH, NHS(O)₂NH, NHS(O)₂NH₂, C(O)NHS(O)₂,C(O)NHS(O)₂NH or C(O)NHS(O)₂NH₂, and the like, groups comprising one ormore functional groups, non-aromatic hydrocarbons (optionallysubstituted), and groups wherein one or more carbons of a non-aromatichydrocarbon (optionally substituted) is replaced by a functional group.Carbon atoms of an aliphatic group can be optionally oxo-substituted. Analiphatic group may be straight chained, branched, cyclic, or acombination thereof and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, as used herein, aliphaticgroups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls,such as polyalkylene glycols, polyamines, and polyimines, for example.Aliphatic groups may be optionally substituted.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused, bridged or spiro system, where (i) each ringsystem contains at least one heteroatom independently selected fromoxygen, sulfur and nitrogen, (ii) each ring system can be saturated orunsaturated (iii) the nitrogen and sulfur heteroatoms may optionally beoxidized, (iv) the nitrogen heteroatom may optionally be quaternized,(v) any of the above rings may be fused to an aromatic ring, and (vi)the remaining ring atoms are carbon atoms which may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic,iminic or oximic double bond. Representative heterocycloalkyl groupsinclude, but are not limited to, 1,3-dioxolane, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinoxalinyl, pyridazinonyl,2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl,5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl,and tetrahydrofuryl. Such heterocyclic groups may be furthersubstituted. Heteroaryl or heterocyclic groups can be C-attached orN-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, alicyclic,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphaticmoiety or the like, described herein can also be a divalent ormultivalent group when used as a linkage to connect two or more groupsor substituents, which can be at the same or different atom(s). One ofskill in the art can readily determine the valence of any such groupfrom the context in which it occurs.

The term “substituted” refers to substitution by independent replacementof one, two, or three or more of the hydrogen atoms with substituentsincluding, but not limited to, —F, —Cl, —Br, —I, —OH, C₁-C₁₂-alkyl;C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, protected hydroxy, —NO₂, —N₃, —CN, —NH₂,protected amino, oxo, thioxo, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₈-alkenyl,—NH—C₂-C₈-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₈-alkenyl,—CONH—C₂-C₈-alkynyl, —CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl,—CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₈-alkenyl, —OCO₂—C₂-C₈-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —CO₂—C₁-C₁₂ alkyl,—CO₂—C₂-C₈ alkenyl, —CO₂—C₂-C₈ alkynyl, CO₂—C₃-C₁₂-cycloalkyl,—CO₂-aryl, CO₂-heteroaryl, CO₂-heterocyloalkyl, —OCONH₂,—OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₈-alkenyl, —OCONH—C₂-C₈-alkynyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl,—OCONH-heterocyclo-alkyl, —NHC(O)H, —NHC(O)—C₁-C₁₂-alkyl,—NHC(O)—C₂-C₈-alkenyl, —NHC(O)—C₂-C₈-alkynyl, —NHC(O)—C₃-C₁₂-cycloalkyl,—NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclo-alkyl,—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₈-alkenyl, —NHCO₂—C₂-C₈-alkynyl,—NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl, —NHCO₂-heteroaryl,—NHCO₂-heterocycloalkyl, —NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl,—NHC(O)NH—C₂-C₈-alkenyl, —NHC(O)NH—C₂-C₈-alkynyl,—NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,—NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH—C₁-C₁₂-alkyl,—NHC(S)NH—C₂-C₈-alkenyl, —NHC(S)NH—C₂-C₈-alkynyl,—NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl,—NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH—C₁-C₁₂-alkyl,—NHC(NH)NH—C₂-C₈-alkenyl, —NHC(NH)NH—C₂-C₈-alkynyl,—NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl,—NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C₁-C₁₂-alkyl,—NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)—C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₈-alkenyl, —C(NH)NH—C₂-C₈-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₈-alkenyl, —SO₂NH—C₂-C₈-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthio-methyl. In certain embodiments, the substituents areindependently selected from halo, preferably Cl and F; C₁-C₄-alkyl,preferably methyl and ethyl; C₂-C₄-alkenyl; halo-C₁-C₄-alkyl, such asfluoromethyl, difluoromethyl, and trifluoromethyl; halo-C₂-C₄-alkenyl;C₃-C₆-cycloalkyl, such as cyclopropyl; —CN; —OH; NH₂; C₁-C₄-alkylamino;di(C₁-C₄-alkyl)amino; and NO₂. It is understood that the substituents,such as the aryls, heteroaryls, alkyls, and the like, are optionallyfurther substituted. In some cases, each substituent in a substitutedmoiety is additionally optionally substituted with one or more groups,each group being independently selected from C₁-C₄-alkyl; CF₃,C₁-C₄-alkoxy; —OCF₃, —F, —Cl, —Br, —I, —OH, —NO₂, —CN, and —NH₂.

It is understood that the aryls, heteroaryls, alkyls, cycloalkyls andthe like can be further substituted.

The term “halo” or “halogen” alone or as part of another substituent, asused herein, refers to a fluorine, chlorine, bromine, or iodine atom.

The term “optionally substituted”, as used herein, means that thereferenced group may be substituted or unsubstituted. In one embodiment,the referenced group is optionally substituted with zero substituents,i.e., the referenced group is unsubstituted. In another embodiment, thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from groups describedherein.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

In certain embodiments, the compounds of each formula herein are definedto include isotopically labelled compounds. An “isotopically labelledcompound” is a compound in which at least one atomic position isenriched in a specific isotope of the designated element to a levelwhich is significantly greater than the natural abundance of thatisotope. For example, one or more hydrogen atom positions in a compoundcan be enriched with deuterium to a level which is significantly greaterthan the natural abundance of deuterium, for example, enrichment to alevel of at least 1%, preferably at least 20% or at least 50%. Such adeuterated compound may, for example, be metabolized more slowly thanits non-deuterated analog, and therefore exhibit a longer half-life whenadministered to a subject. Such compounds can synthesize using methodsknown in the art, for example by employing deuterated startingmaterials. Unless stated to the contrary, isotopically labelledcompounds are pharmaceutically acceptable.

The term “hydroxy activating group,” as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxyl,” as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl,benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl,trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group,” as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992) and in “Prodrugs of Alcohols and Phenols” by S. S. Dhareshwar andV. J. Stella, in Prodrugs Challenges and Rewards Part-2, (Biotechnology:Pharmaceutical Aspects), edited by V. J. Stella, et al, Springer andAAPSPress, 2007, pp 31-99.

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl,benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “amino acid” refers to naturally occurring and synthetic α, β,γ, or δ amino acids, and includes but is not limited to, amino acidsfound in proteins or intermediates in metabolism of amino acids orproteins, i.e. glycine, alanine, valine, leucine, isoleucine,methionine, phenylalanine, tryptophan, proline, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,citrulline, arginine and histidine. In certain embodiments, the aminoacid is in the L-configuration. In certain embodiments, the amino acidis in the D-configuration. In certain embodiments, the amino acid isprovided as a substituent of a compound described herein, wherein theamino acid is a residue selected from the group consisting of alanyl,valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl,methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl,asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl,histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleuccinyl, β-prolinyl,β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl,β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl,β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl and β-histidinyl.

The term “amino acid derivative” refers to a group derivable from anaturally or non-naturally occurring amino acid, as described andexemplified herein. Amino acid derivatives are apparent to those ofskill in the art and include, but are not limited to, ester, aminoalcohol, amino aldehyde, amino lactone, and N-methyl derivatives ofnaturally and non-naturally occurring amino acids. In an embodiment, anamino acid derivative is provided as a substituent of a compounddescribed herein, wherein the substituent is —NR^(u)-G(S_(c))—C(O)-Q¹,wherein Q¹ is —SR^(v), —NR^(v)R^(v) or alkoxyl, R^(v) is hydrogen oralkyl, S_(c) is a side-chain of a naturally occurring or non-naturallyoccurring amino acid, G is C₁-C₂ alkyl, and R^(u) is hydrogen; or R^(u)and S_(c) are taken together with the atoms to which they are attachedto form a five-membered heterocyclic ring. In an embodiment, an aminoacid derivative is provided as a substituent of a compound describedherein, wherein the substituent is —O—C(O)-G(S_(c))—NH-Q², wherein Q² ishydrogen or alkoxyl, S_(c) is a side-chain of a naturally occurring ornon-naturally occurring amino acid and G is C₁-C₂ alkyl. In certainembodiments, Q² and S_(c) are taken together with the atoms to whichthey are attached to form a five-membered heterocyclic ring. In certainembodiments, G is an optionally substituted methylene and S_(c) isselected from the group consisting of hydrogen, alkyl, arylalkyl,heterocycloalkyl, carboxylalkyl, heteroarylalkyl, aminoalkyl,hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl, sulfanylalkyl,carbamoylalkyl, alkylsulfanylalkyl and hydroxylarylalkyl. In anembodiment, an amino acid derivative is provided as a substituent of acompound described herein, wherein the amino acid derivative is in theD-configuration. In an embodiment, an amino acid derivative is providedas a substituent of a compound described herein, wherein the amino acidderivative is in the L-configuration.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, N Y, 1986.

The term “protic solvent,” as used herein, refers to a solvent thattends to provide protons, such as an alcohol, for example, methanol,ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Suchsolvents are well known to those skilled in the art, and it will beobvious to those skilled in the art that individual solvents or mixturesthereof may be preferred for specific compounds and reaction conditions,depending upon such factors as the solubility of reagents, reactivity ofreagents and preferred temperature ranges, for example. Furtherdiscussions of protogenic solvents may be found in organic chemistrytextbooks or in specialized monographs, for example: Organic SolventsPhysical Properties and Methods of Purification, 4th ed., edited by JohnA. Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable,” as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the Formula herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, 2^(nd) Ed. Wiley-VCH (1999); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject,” as used herein, refers to an animal. Preferably, theanimal is a mammal. More preferably, the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus, acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

Certain compounds of the present invention may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of these compounds and mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt,” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentane-propionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, esters ofC₁-C₆-alkanoic acids, such as acetate, propionate, butyrate and pivalateesters.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intra-arterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose, any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectable.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to Van Devanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference).

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 50 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections, conditions are treated or prevented in a patient such as ahuman or another animal by administering to the patient atherapeutically effective amount of a compound of the invention, in suchamounts and for such time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the present invention described herein can, forexample, be administered by injection, intravenously, intra-arterial,subdermally, intraperitoneally, intramuscularly, or subcutaneously; ororally, buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically excipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the Formula described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The said “additional therapeutic or prophylactic agents” includes butnot limited to, immune therapies (eg. interferon), therapeutic vaccines,antifibrotic agents, anti-inflammatory agents such as corticosteroids orNSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines(e.g. theophylline), mucolytic agents, anti-muscarinics,anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists),anti-oxidants (e.g. N-acetylcysteine), cytokine agonists, cytokineantagonists, lung surfactants and/or antimicrobial and anti-viral agents(e.g. ribavirin and amantidine). The compositions according to theinvention may also be used in combination with gene replacement therapy.

Combination and Alternation Therapy for HBV

It has been recognized that drug-resistant variants of HIV, HBV and HCVcan emerge after prolonged treatment with an antiviral agent. Drugresistance most typically occurs by mutation of a gene that encodes fora protein such as an enzyme used in viral replication, and mosttypically in the case of HIV, reverse transcriptase, protease, or DNApolymerase, and in the case of HBV, DNA polymerase, or in the case ofHCV, RNA polymerase, protease, or helicase. Recently, it has beendemonstrated that the efficacy of a drug against HIV infection can beprolonged, augmented, or restored by administering the compound incombination or alternation with a second, and perhaps third, antiviralcompound that induces a different mutation from that caused by theprinciple drug. The compounds can be used for combinations and areselected from the group consisting of an HBV polymerase inhibitor,interferon, TLR modulators such as TLR-7 agonists or TLR-9 agonists,therapeutic vaccines, immune activator of certain cellular viral RNAsensors, viral entry inhibitor, viral maturation inhibitor, distinctcapsid assembly modulator, antiviral compounds of distinct or unknownmechanism, and combination thereof. Alternatively, the pharmacokinetics,biodistribution, or other parameter of the drug can be altered by suchcombination or alternation therapy. In general, combination therapy istypically preferred over alternation therapy because it induces multiplesimultaneous stresses on the virus.

Preferred compounds for combination or alternation therapy for thetreatment of HBV include 3TC, FTC, L-FMAU, interferon, adefovirdipivoxil, entecavir, telbivudine (L-dT), valtorcitabine (3′-valinylL-dC), β-D-dioxolanyl-guanine (DXG), β-D-dioxolanyl-2,6-diaminopurine(DAPD), and β-D-dioxolanyl-6-chloropurine (ACP), famciclovir,penciclovir, lobucavir, ganciclovir, and ribavirin.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBNfor azobisisobutyronitrile; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc₂O fordi-tert-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for1-methyl-1-(4-biphenylyl)ethyl carbonyl; Bz for benzoyl; Bn for benzyl;BocNHOH for tert-butyl N-hydroxycarbamate; t-BuOK for potassiumtert-butoxide; Bu₃SnH for tributyltin hydride; BOP for(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumHexafluorophosphate; Brine for sodium chloride solution in water; BSAfor N,O-bis-(trimethyl silyl)acetamide; CDI for carbonyldiimidazole;CH₂Cl₂ for dichloromethane; CH₃ for methyl; CH₃CN for acetonitrile;Cs₂CO₃ for cesium carbonate; CuCl for copper (I) chloride; CuI forcopper (I) iodide; dba for dibenzylidene acetone; dppb fordiphenylphos-phinobutane; DBU for 1,8-diazabicyclo[5.4.0]-undec-7-ene;DCC for N,N′-dicyclohexyl-carbodiimide; DEAD fordiethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIPEA or(i-Pr)₂EtN for N,N,-diisopropylethyl amine; Dess-Martin periodinane for1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP for4-dimethylamino-pyridine; DME for 1,2-dimethoxyethane; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT fordi(methoxyphenyl)-phenylmethyl or dimethoxytrityl; DPPA fordiphenylphosphoryl azide; EDC forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide; EDC HCl forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; EtOAc forethyl acetate; EtOH for ethanol; Et₂O for diethyl ether; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniumHexafluoro-phosphate; HCl for hydrogen chloride; HOBT for1-hydroxybenzotriazole; K₂CO₃ for potassium carbonate; n-BuLi forn-butyl lithium; i-BuLi for i-butyl lithium; t-BuLi for t-butyl lithium;PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP forlithium 2,2,6,6-tetramethyl-piperidinate; MeOH for methanol; Mg formagnesium; MOM for methoxymethyl; Ms for mesyl or —SO₂—CH₃; Ms₂O formethanesulfonic anhydride or mesyl-anhydride; MTBE for t-butyl methylether; NaN(TMS)₂ for sodium bis(trimethylsilyl)amide; NaCl for sodiumchloride; NaH for sodium hydride; NaHCO₃ for sodium bicarbonate orsodium hydrogen carbonate; Na₂CO₃ for sodium carbonate; NaOH for sodiumhydroxide; Na₂SO₄ for sodium sulfate; NaHSO₃ for sodium bisulfite orsodium hydrogen sulfite; Na₂S₂O₃ for sodium thiosulfate; NH₂NH₂ forhydrazine; NH₄HCO₃ for ammonium bicarbonate; NH₄Cl for ammoniumchloride; NMO for N-methyl-morpholine N-oxide; NaIO₄ for sodiumperiodate; Ni for nickel; NSFI for N-fluorobenzene-sulfonimide; OH forhydroxyl; o/n for overnight; OsO₄ for osmium tetroxide; PTSA forp-toluenesulfonic acid; PPTS for pyridinium p-toluenesulfonate; TBAF fortetrabutyl-ammonium fluoride; TEA or Et₃N for triethylamine; TES fortriethylsilyl; TESCl for triethylsilyl chloride; TESOTf fortriethylsilyl trifluoro-methanesulfonate; TFA for trifluoroacetic acid;THF for tetrahydro-furan; TMEDA forN,N,N′,N′-tetramethylethylene-diamine; TPP or PPh₃ fortriphenyl-phosphine; Troc for 2,2,2-trichloroethyl carbonyl; Ts fortosyl or —SO₂—C₆H₄CH₃; Ts₂O for tolylsulfonic anhydride ortosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for palladium; Ph forphenyl; POPd for dihydrogendichlorobis(di-tert-butylphosphinito-κP)palladate(II); Pd₂(dba)₃ fortris(dibenzylideneacetone) dipalladium (0); Pd(PPh₃)₄ fortetrakis(triphenyl-phosphine)palladium (0); PdCl₂(PPh₃)₂ fortrans-dichlorobis-(triphenylphosphine)palladium (II); Pt for platinum;Rh for rhodium; rt for room temperature; Ru for ruthenium; SFC forsupercritical fluid chromatography; TBS for tert-butyl dimethylsilyl;TMS for trimethylsilyl; or TMSCl for trimethylsilyl chloride.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared. These schemes are of illustrative purpose and are not meant tolimit the scope of the invention. Equivalent, similar, or suitablesolvents, reagents or reaction conditions may be substituted for thoseparticular solvents, reagents, or reaction conditions described hereinwithout departing from the general scope of the method of synthesis.Certain reactions can be conducted as generally described in WO2017/136403.

The compounds of the Formula I may be prepared via several differentsynthetic routes from a variety of optionally substituted phenyl,heteroaryl, or fused bicyclic aryl or heteroaryl precursors using thechemical transformations that are known to those skilled in the art.Strategistically, a compound of Formula I can be constructed to form thesulfonyl group at the right end followed by formation of group A at theleft end. Alternatively, a compound of Formula I can be constructed toform the group A at the left end followed by formation of sulfonyl groupat the right end. The preparation of sulfones can be realized by eitheroxidation of sulfide (reviewed by K. Schank, The Chemistry of Sulfonesand Sulfoxides, Wiley, N.Y. 1988, Chap. 7) or alkylation/arylation of alow-valent sulfur species such as sulfinate salts (reviewed by G. Liu,C. Fan, J. Wu, Org. Biomol. Chem. 2015, 13, 1592). A sulfide can besynthesized from a thiol precursor via a nucleophilic substitution to anorganic halide or sulfonate ester, or a nucleophilic addition to anepoxide, aziridine, or unsaturated substrate (reviewed by G. Solladie,Comprehensive Organic Synthesis, 1991, Vol 6, 133), or a radicaladdition of thiol to an unsaturated substrate. A sulfinate salt can beaccessed either by reduction of a sulfonyl halide (reviewed by Schubart,R. Sulfinic Acids and Derivatives, Ullmann's Encyclopedia of IndustrialChemistry, 2000, 677) or by transition metal catalyzed reaction of arylor hetero aryl halide (A. Shavnya, S. S. Coffey, A. C. Smith, V.Mascitti, Org. Lett., 2013, 15, 6226) or boronic acid (A. Shavnya, K. D.Hesp, V. Mascitti, A. C. Smith, Angew. Chem. Int. Ed., 2015, 54, 13571)with potassium metabisulfite. A sulfone compound may be furtherfunctionalized by deprotonation with a strong base followed by reactionof the resultant anion with an electrophile such as an organic halide,aldehyde, ketone, electrophilic halogenation reagent, or an unsaturatedsubstrate such as a Michael addition acceptor; a tertiary sulfone may beprepared from a primary sulfone through a two-round sequentialdeprontonation and anionic nucleophilic reaction. An amide bond can beformed either by reaction of an acid halide or anhydride with an amineor by the direct coupling of a carboxylic acid with an amine in thepresence of a coupling reagent such as DCC, EDC, or HATU.

As illustrated in Scheme 1, wherein X, Y and R are as definedpreviously; LG₁, LG₂ at each occurrence are leaving groups and are eachindependently selected from halogen, tosylate, mesylate and triflate. Inone approach, an optionally substituted aryl or heteroaryl amine 1-1 canreact selectively with various acid chloride 1-2 in a solvent such asbut not limited to toluene, tetrahydrofuran, dichloromethane or amixture of thereof, optionally in the presence of a base such as but notlimited to triethylamine, DIPEA, or pyridine, to provide a variety ofamide intermediates 1-3. 1-3 is then treated with a reducing reagentsuch as but not limited to triphenylphosphine, SnCl₂, Sn/HCl, Zn/HCl, orPd/HCOOH, to provide thiol intermediate 1-4, which reacts withintermediate 1-5 by a nucleophilic displacement fashion optionally inthe presence of a base such as but not limited to potassium carbonate,sodium carbonate, triethylamine or DIPEA to afford a sulfideintermediate which is transformed to a compound of Formula IIa in asuitable solvent in the presence of a oxidizing reagent such as but notlimited to hydrogen peroxide, meta-chloroperbenzoic acid, perbenzoicacid or tert-butyl peroxide. Alternatively, carboxylic ester 1-6 isconverted to sulfone intermediate 1-7 using chemistry similar to thatdescribed above or by nucleophilic substitution with an organometallicagent (R-M, wherein M is a Mg- or Zn-species). 1-7 can be saponifiedwith a base, such as but not limited to lithium hydroxide, sodiumhydroxide, or potassium hydroxide, to yield carboxylic acid 1-8. Theacid 1-8 can react with amine 1-1 in the presence of coupling reagentsuch as but not limited to DCC, EDC, or HATU, in a suitable solvent,optionally in the presence of a base such as but not limited totriethylamine, DIPEA, or pyridine, to yield the compound of Formula IIa.

The preparation of the compound of Formula IIb is described below inScheme 2. An aldehyde 2-1 is reacted with TMSCF₃ to give atrifluoroethyl alcohol 2-2, which is converted to a triflate by reactingwith Tf₂O in the presence of base such as DIPEA, followed bydisplacement with amine X—NH₂ to afford the compound of Formula

The synthesis of the compound of Formula IIc containing an aminooxetanylmoiety is exemplified in Scheme 3. An arylamine or heteroarylamine 3-1is condensed with oxetan-3-one in the presence of an acid such as aceticacid or p-TsA to give imine 3-2, which is treated with a nucleophilic3-3, wherein M₁ is an organometallic species including but not limitedto that related to boronic acid/ester, organotin, organozinc,organolithium, or organomagesium moiety, to afford compound of formulaIIc.

As shown in Scheme 4, the compound of Formula IId may be prepared fromthe compound of formula IIa. IIa may react with benzyl bromide in thepresence of a base such as but not limited to NaH or LDA, to givecompound 4-1, which is converted to a compound 4-2 by reacting withoxalyl chloride, followed by treatment with a fluorinating reagent suchas but not limited to DAST, SF₄ or Et₃N—HF. Compound 4-2 may be treatedwith hydrogen gas in the presence a suitable catalyst such as but notlimited to Pd/C, PtO₂, or Pd(OH)₂/C, to afford compound of Formula IId.

It will be appreciated that, with appropriate manipulation andprotection of any chemical functionality, synthesis of compounds ofFormula I is accomplished by methods analogous to those above and tothose described in the Experimental section. Suitable protecting groupscan be found, but are not restricted to, those found in T W Greene and PG M Wuts “Protective Groups in Organic Synthesis”, 3rd Ed (1999), JWiley and Sons.

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Intermediate 1

Step Int 1a. A mixture of 4-chloro-3-(chlorosulfonyl)-benzoic acid (0.86g, 3.4 mmol) in SOCl₂ (5.0 mL) was heated to reflux overnight. It wasconcentrated to give the desire crude product, which was used for thenext step directly.

Step Int 1b. The compound from Step Int 1a (0.91 g, 3.3 mmol) and3,4,5-trifluoroaniline (0.49 g, 3.3 mmol) in toluene (10 mL) was stirredat 90° C. overnight. It was concentrated to give the crude desiredcompound, which was used for the next step directly.

Step Int 1c. The compound from Step Int 1b (0.89 g, 2.3 mmol) andtriphenylphosphine (3.4 g, 13 mmol) in toluene (12 mL) was stirred at80° C. for 4 h. It was diluted with EtOAc and washed with sat. aq.NaHCO₃ and brine. The organic was dried (Na₂SO₄), filtered andconcentrated. The residue was chromatographed (silica, hexanes/EtOAc) togive the desired compound as white solid (0.49 g, 71%). ESI-MSm/z=316.0, 318.0 [M−H]⁻.

Intermediate 2

Step Int 2a. A mixture of 2-methylenepropane-1,3-diyl diacetate (2.69 g,15.62 mmol), Pd(OAc)₂ (0.210 g, 0.937 mmol), Ph₃P (0.983 g, 3.75 mmol),and 1-(cyclopent-1-en-1-yl)pyrrolidine (3.19 ml, 21.86 mmol) inacetonitrile (89 ml) was heated to and remained at 65° C. for 18 hours.Water (45 ml) was added and the reaction mixture was stirred for 1 hour.Saturated brine was added and it was extracted with ethyl acetate. Theorganic phase was dried (Na₂SO₄), filtered and concentrated. The residuewas chromatographed (silica, hexanes/EtOAc) to give the desired compound(1.53 g, 71.9% yield) as a colorless oil.

Step Int 2b. A solution of the compound from step Int 2a (41.725 g, 306mmol) in THF (300 mL) was cooled to −78° C. followed by addition ofLiAlH₄ (1M in THF, 92 mL, 92 mmol). After being stirred for 15 minutes,it was quenched by water (3.4 mL), NaOH (1M, 3.4 mL) and water (10.2mL). The organic was dried (Na₂SO₄), filtered over Celite andconcentrated to give the crude desired compound (48.4 g, 97%, contains15% THF w/w), which was used for the following step.

Step Int 2c. To a stirred compound from step Int 2b (50.7 g, 367 mmol)and imidazole (62.4 g, 58.8 mmol) in DMF (400 mL) at 0° C. was addedTBSCl (66.3 g, 440 mmol). The resulting reaction mixture was stirred atrt for 16 h. The reaction was diluted with hexanes and the mixture waswashed with water, brine. The organic layer was dried (Na₂SO₄), filteredand concentrated to give the desired compound as white solid (101.0 g,100%).

Step Int 2d. A suspension compound from step Int 2c (101 g, 368 mmol) indioxane-water (1.1 L/0.36 L) at rt was added 2,6-dimethylpyridine (86ml, 735 mmol), osmium(VIII) oxide (1.87 g, 7.35 mmol) and sodiumperiodate (280 g, 1.31 mol) and the mixture was stirred at rt for 20 h.It was quenched with aqueous Na₂S₂O₃, extracted with MBTE, washed withwater, brine, dried over Na₂SO₄, filtered, concentrated to give desiredproduct as white solid (100 g, 99%).

Step Int 2e. To a solution of the compound of step Int 2d (118.5 g, 466mmol) in MTBE (1.2 L) at 0° C. was added LiBH₄ (314 mL, 629 mmol, 2M inTHF). The resulting reaction mixture was stirred at 0° C. for 2 h. Thereaction was quenched with aqueous NH₄Cl and the mixture was extractedwith MBTE, washed with water, brine. The organic layer was dried(Na₂SO₄), filtered and concentrated. The crude product was used withoutfurther purification (117 g, 98%, 10:1 dr favoring the desired isomer).

Step Int 2f. To a stirred solution from step Int 2e (315 mg, 1.23 mmol)and compound from step 1c (390 mg, 1.23 mmol) in toluene (5 ml) wasadded 2-(tributyl-15-phosphanylidene)acetonitrile (0.81 ml, 3.07 mmol),and the mixture was stirred at 100° C. for 60 h. It was cooled to rt,diluted with MBTE, washed with NaOH (0.5 N), brine, dried over Na₂SO₄,filtered, concentrated, silica column to desired compound (362 mg, 53%).ESI-MS m/z=554.15, 556.15 [M−H]⁻.

Step Int 2g. A suspension of compound from step Int 2f (0.53 g, 0.95mmol) in MeOH (11 mL) at rt was added con HCl (1.0 mL) and stirred at rtfor 24 h. It was concentrated under vacuum to remove majority of MeOHand the residue was extracted with EtOAc. The organic phase was washedwith water, 10% K₂CO₃, brine, dried over Na₂SO₄, filtered, concentratedand recrystallized from EtOAc/hexanes to give desired product as a whitesolid (0.33 g, 78%). ESI-MS m/z=440.07, 442.07 [M−H]⁻.

Step Int 2h. A solution of compound from step Int 2g (1.8 g, 3.8 mmol)in DMSO (10 mL) at rt was added IBX (4.3 g, 15.3 mmol) and the mixturewas stirred at rt for 20 h. Aqueous Na₂S₂O₃NaHCO₃ and few drops of Et₃Nwas added and stirred at rt for 1 h. It was extracted with EtOAc, washedwith water, brine, dried over Na₂SO₄, filtered and concentrated to givethe title compound (1.65 g, 92%). ESI-MS m/z=470.04, 472.04 [M−H]⁻.

Intermediate 3

Step Int 3a. To a solution of Int 2 (1.76 g, 4.0 mmol) andtrimethyl-sulfoxonium iodide (1.76 g, 8.0 mmol) in DMSO (20 mL) at 0° C.was added t-BuOK (1.12 g, 10 mmol). The resulting reaction mixture wasstirred at rt for 1 h. The reaction was quenched with aqueous NH₄Cl andthe mixture was extracted with EtOAc, washed with water, brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated. The crudeproduct was chromatographed (silica, hexanes/EtOAc) to give the desiredcompound as white solid (1.36 g, 75%). ESI-MS m/z=452.07, 454.07 [M−H]⁻.

Step Int 3b. To a stirred solution of compound from step Int 3a (78 mg,0.17 mmol) in DMF (2.5 mL) was added NH₄Cl (17 mg, 0.32 mmol) and NaN₃(44 mg, 0.67 mmol) then stirred at 60° C. for 24 h. It was diluted withEtOAc, washed with water, brine, dried over Na₂SO₄, filtered, Con,chromatographed (silica, hexanes/EtOAc) to give the desired compound aswhite solid (73 mg, 88%). ESI-MS m/z=495.08, 497.08 [M−H]⁻.

Step Int 3c. To a solution of compound from step Int 3b (0.20 g, 0.40mmol) in NMP (2.0 mL) was added m-CPBA (0.27 g 77%, 1.2 mmol) andstirred at rt O/N. Aqueous Na₂S₂O₃, NaHCO₃ and few drops of Et₃N wasadded and stirred at rt for 1 h. It was extracted with EtOAc, washedwith water, brine, dried over Na₂SO₄, filtered, concentrated andchromatographed (silica, hexanes/EtOAc) to give the desired compound aswhite solid (0.21 g, 98%). ESI-MS m/z=527.07, 529.07 [M−H]⁻.

Step Int 3d. Into the solution of example 257 (540 mg, 1.02 mmol) inMeOH (2 mL) and THF (1 mL), Raney nickel (washed with MeOH, 50 mg) wasadded. A balloon filled with hydrogen was introduced. It was stirred 2hours at rt. The mixture was filtered through a pad of celite, washedwith MeOH. The filtrated was concentrated to give the title compound(440 mg, 86%). ESI-MS m/z=501.08, 503.08 [M−H]⁻.

Intermediate 4

Step Int 4a. To a solution of compound from step Int 2b (7.7 g, 77.18%in THF, 43 mmol) in anhydrous dichloromethane (20 mL) at 0° C. was addedDBU (7.9 g, 5.2 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonylfluoride (14.4 g, 48 mmol). The reaction was kept at 0° C. for 0.5 hbefore it was concentrated to dry. The residue was dissolved in hexane(70 mL). The solution was washed with HCl (0.5 M), water, NaHCO₃, brineand dried (Na₂SO₄). It was filtered through a layer of silica gel,washed with hexane (300 mL) and concentrated to give colorless oil (16.8g 92%). ¹HNMR (400 MHz, CDCl₃) δ 5.13 (t, 1H), 4.85 (s, 2H), 2.67 (d,2H), 2.46 (brs, 2H), 2.04 (dd, 2H), 1.72 (m, 2H), 1.58 (m, 2H).

Step Int 4b. A mixture of compound from step Int 4a (2.101 g, 5 mmol)and 4-methylmorpho-line 4-oxide (0.703 g, 6.00 mmol) in acetone-water(4.5 mL/0.5 mL) at rt was added osmium(VIII) oxide (0.628 ml, 2.5% int-BuOH) and stirred at rt o/n. Na₂S₂O₃ (1.58 g, 10 mmol) and water (2mL) was added stirred at rt for 30 mins. It was partitioned(EtOAc/water). The organic was washed with 1N HCl, aq. NaHCO₃, brine anddried (Na₂SO₄). After filtered, the crude was concentrated to give thedesired product (2.24 g, 99%). ¹HNMR (400 MHz, CDCl₃) δ 5.03 (t, 1H),3.60 (s, 2H), 2.44 (brs, 2H), 1.99 (ddd, 4H), 1.82 (m, 4H), 1.61 (m,2H).

Step Int 4c. To a suspension of the compounds from step Int 4b (1.84 g,5.81 mmol), triphenylphophine (0.063 g, 0.024 mmol) in THF (4 mL) at rtwas degassed followed by addition of Potassium t-butoxide (1M in THF,5.32 mL, 5.32 mmol). In 5 minutes, the compound from step 1c (2.2 g,4.84 mmol) in THF (9 mL) was added and stirred at 60° C. for 24 h. Afterbeing cooled, it was diluted with MBTE (60 mL), filtered and washed withMTBE. The combined solution was washed with 0.5 N NaOH, brine and dried(Na₂SO₄). It was filtered through a short silica plug (10 g silica gel)and washed with EtOAc (50 mL). The combined organic was concentratedunder vacuum to give crude 2.5 g (110%).

Step Int 4d. To the solution of the compound from step Int 4c (1.80 g,3.81 mmol) in NMP (5 mL), m-CPBA (77 wt %, 2.14 g, 9.54 mmol) was added.It was stirred at rt for 20 hours before aq. NaS₂O₃ (3 mL) was addedfollowed by aq. NaHCO₃ (3 mL) and MeOH (5 mL). The white solid wascollected under vacuum and washed with aq. NaHCO₃, water. This mixturewas further recrystallized from MeOH to give the title compound (1.7 g,87%). ESI-MS m/z=502.07, 504.07 [M−H]⁻.

Intermediate 5

To a mixture of compound from intermediate 4 (2.00 g, 3.97 mmol), DIPEA(3.47 mL, 19.84 mmol), and DMSO (6.2 ml, 87 mmol) in DCM (12 ml) wasadded SO₃ pyridine complex (1.895 g, 11.9 mmol). The reaction wasstirred at rt for 3 h. It was diluted with EtOAc and washed with 1M HCland brine. The organic was dried (Na₂SO₄), filtered and concentrated.The residue was chromatographed (silica, hexanes/acetone) to give thetitle compound (1.59 g, 3.18 mmol, 80% yield). ESI-MS m/z=500.05, 502.05[M−H]⁻.

Intermediate 6

The title compound was prepared using procedures similar to thatdescribed in Intermediate 1. ESI-MS m/z=297.99, 299.99 [M−H]⁻.

Example 1

Step 1a. Into the solution of Intermediate 3 (50 mg, 0.10 mmol) and(tert-butoxycarbonyl)-L-proline (26 mg, 0.12 mmol) in DMF (1.0 mL) wasadded DIPEA (0.051 mL, 0.30 mmol) and HATU (45 mg, 0.12 mmoL). It wasstirred 2 hours at rt and purified on prep-HPLC (C-18,Acetonitrile/water) to afford the desired compound as a white solid (20mg, 29%). ESI-MS m/z=698.19, 700.19 [M−H]⁻.

Step 1b Into the solution of compound from step 1a (16 mg, 0.023 mmol)in THF (0.4 mL) was added HCl (4M in dioxane, 0.4 mL, 1.6 mmol). It wasstirred 3 hours at rt and concentrated to afford the desired compound asa white solid (14 mg, 99%). ESI-MS m/z=598.14, 600.14 [M−H]⁻.

Step 1c. Into the solution of compound from step 1b (12 mg, 0.019 mmol),formaldehyde (0.1 mL 37% aqueous solution) and DIPEA (0.033 mL, 0.019mmol) and a few drop of acetic acid in THF (0.5 mL) was added NaBH(OAc)₃(12 mg, 0.057 mmoL). It was stirred 2 hours at rt and sat. aqueousNaHCO₃ was added. It was extracted with EtOAc, washed with water, brine,dry over anhydrous Na₂SO₄, filtered, concentrated and the crude waspurified on prep-HPLC (C-18, Acetonitrile/water) to afford the titlecompound as a white solid (8.2 mg, 71%). ESI-MS m/z=612.12, 614.12[M−H]⁻.

Example 3

To the solution of compounds from intermediate 4 (30 mg, 0.06 mmol),sulfamoyl chloride (8.5 mg, 0.072 mmol) in THF (0.5 mL) at rt was addedTEA (4 drops) and the mixture was stirred at rt for 3 hours. It wasconcentrated and was purified by prep-HPLC (C18 column,acetonitrile/water) eluent to give title compound (13.5 mg, 38%). ESI-MSm/z=581.04, 583.04 [M−H]⁻.

Example 4

Step 4a. To the solution of intermediate 2 (880 mg, 2.0 mmol), in THF(10 mL) at 0° C. was added prop-1-en-1-ylmagnesium chloride 0.5 M, 12mL) and the solution was stirred at such temperature for 30 minutesbefore it was quenched with a NH₄Cl (20 mL). It was extracted withEtOAc, the organic was washed with brine, dried (Na₂SO₄), filtered andconcentrated. The crude was chromatographed (silica, ethylacetate/hexanes) to give the desired compounds Z-isomer (252 mg, 26%yield) as a white solid and E-isomer (596 mg, 61%) ESI-MS m/z=502.09,504.07 [M−H]⁻.

Step 4b. To the solution of Z-isomer of step 4a (252 mg, 0.523 mmol) andNMO (123 mg, 1.05 mmol) in acetone (5 mL)/water (1 mL) was added OsO4(4% in t-BuOH, 0.066 mL, 0.01 mmol) and the solution was stirred at rto/n. It was dilute with EtOAc, wash with Na₂S₂O₃, NaHCO₃, water andbrine and concentrated. This crude was dissolved in THF (3 mL). m-CPBA(77 w %, 234 mg, 1.1 mmol) was added and stirred at rt o/n. Afterquenched with aq. Na₂SO₃ and aq. NaHCO₃, it was extracted with EtOAcbefore it was dried and concentrated. The crude was crystallized fromhot MeOH to give the title compound (223 mg, 78%, racemic) as whitesolid. ESI-MS m/z=546.06, 548.06 [M−H]⁻.

Example 5

The title compound (racemic, white solid) was prepared from the E-isomerof Step 4a following similar procedures described in Step 4b. ESI-MSm/z=546.06, 548.06 [M−H]⁻.

Example 6

Step 6a. To a mixture of the compound from Step Int 2b (1.400 g, 4.67mmol) and Intermediate 6 (0.922 g, 5.14 mmol) in toluene (30 ml) at rtwas added triphenylphosphine (1.715 g, 6.54 mmol), followed by DIAD(1.181 ml, 6.07 mmol) dropwise. The mixture was stirred at 95° C.overnight before being allowed to cool down to rt and directly purifiedby column chromatography (silica, hexanes/EtOAc) to afford the desiredproduct as a white crystal (1.760 g, 90%). ESI-MS m/z=418.07, 420.06[M−H]⁻.

Step 6b. To a clear solution of the compound from step 6a (1.760 g, 4.19mmol) in THF (40 ml) and water (0.5 ml) at rt was added NMO (2.455 g,20.96 mmol), followed by osmium tetroxide (4 wt % in water, 1.644 ml,0.210 mmol) dropwise. The mixture was stirred at rt overnight. Moreosmium tetroxide (4 wt % in water, 1.644 ml, 0.210 mmol) was added. Theyellow solution was stirred at rt overnight. Saturated Na₂S₂O₃ solutionwas added to quench the reaction. After 20 min at rt, the mixture wasdiluted with THF. The aqueous layer was back-extracted with THF (*1).The combined organic layers were washed with brine (*2), dried overNa₂SO₄ (s), filtered and concentrated. The residual solid wasrecrystallized from boiling MeOH (40 ml) to afford the desired productas a white crystal (1.620 g, 80%). ESI-MS m/z=484.04, 486.04 [M−H]⁻.

Step 6c. To a solution of the compound from step 6b (1.320 g, 2.72 mmol)and DIPEA (2.467 ml, 14.13 mmol) in DCM (8 ml) and DMSO (4.24 ml) cooledat 0° C. was added sulfur trioxide pyridine complex (1.340 g, 8.42mmol). The resulting solution was stirred at 0° C. for 4 h. The mixturewas diluted with EtOAc/THF and then washed with 0.1 N HCl aq (*2), water(*1), and brine (*1). The organic layer was dried over Na₂SO₄ (s),filtered and concentrated. The solid was dissolved in DCM/THF (1/1) andpurified by filtering through a short column (silica, hexanes/THF) toafford the desired product as an off-white foam (1.420 g, quantitativeyield). ESI-MS m/z=482.04, 484.04 [M−H]⁻.

Step 6d. To a solution of the compound from step 6c (0.150 g, 0.310mmol) in DMSO (3 ml) and 7 N ammonia in methanol (1.328 ml, 9.30 mmol)at rt was added glyoxal (40% in water, 0.071 ml, 0.620 mmol). Theresulting solution was stirred at rt overnight. The mixture was freed ofvolatiles. The remaining solution was directly purified by HPLC (40˜90%CH₃CN in H₂O) to afford the title compound as a white solid (42.0 mg,26%). ESI-MS m/z=520.07, 522.07 [M−H]⁻.

Example 7

Step 7a. To a solution of the compound from step 6c (0.120 g, 0.248mmol) in THF (4 ml) cooled at −78° C. was added methylmagnesium bromide(3 M in Et₂O, 0.413 ml, 1.240 mmol) dropwise. The reaction mixture wasstirred at −78° C. for 30 min. More methylmagnesium bromide (3 M inEt₂O, 0.413 ml, 1.240 mmol) was added. The reaction mixture was stirredat −78° C. for 2 h before being allowed to warm to rt and quenched withsaturated NH₄Cl solution. The mixture was diluted with THF and water.The organic layer was washed with brine (*2), dried over Na₂SO₄ (s),filtered and concentrated. The residue was dissolved in DMSO (4 ml) andpurified by HPLC (40˜90% ACN in water) to afford the title compound as awhite solid (39.0 mg, 31%, racemic). ESI-MS m/z=498.07, 500.07 [M−H]⁻.

Example 9

Step 9a. A solution of ethyl 2-(diethoxyphosphoryl)acetate (673 mg, 3.0mmol) in THF (10 mL) was treated with NaH (60% w/w, 120 mg, 3.0 mmol) atrt for 30 minutes before intermediate 5 (502 mg, 1.0 mmol) was added. Itwas stirred o/n at rt. It was diluted with EtOAc and washed with aq.NH₄Cl and brine. The organic was dried (Na₂SO₄), filtered andconcentrated. The residue was chromatographed (silica, hexanes/acetone)to give the desired compound (280 mg, 49%). ESI-MS m/z=570.09, 572.09[M−H]⁻.

Step 9b. Into the solution of step 9a (80 mg, 0.14 mmol) in THF (1mL)/EtOH (1 mL), NaBH₄ (16 mg, 0.42 mmol) was added and stirred at rtfor 2 hours before 2^(nd) portion NaBH₄ (20 mg) was added. It wasstirred for another 3 hours before it was quenched with water, extractedwith EtOAc. The organic was dried (Na₂SO₄), filtered and concentrated.The crude was purified by prep-HPLC (C18 column, acetonitrile/water) togive the title compound (13.5 mg, 38%). ESI-MS m/z=530.08, 532.08[M−H]⁻.

Example 10

Step 10a. To a solution of triethyl phosphonoacetate (0.520 ml, 2.60mmol) THF (5.0 mL) at 0° C. was added NaH (0.104 g 60%, 2.6 mmol). Theresulting reaction mixture was stirred at 0° C. for 30 mins. A solutionof intermediate 2 (0.15 g, 0.34 mmol) in THF (2.0 mL) was added andstirred at rt for 2 h. The reaction was quenched with aqueous NH₄Cl andthe mixture was extracted with EtOAc, washed with water, brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated. The crudeproduct was chromatographed (silica, hexanes/EtOAc) to give the desiredcompound as white solid (0.50 g, 98%). ESI-MS m/z=508.10, 510.10 [M−H]⁻.

Step 10b. To a solution of compounds from step 10a (0.32 g, 0.627 mmol)in THF (5.0 mL) at −78° C. was added DibAL-H (2.5 mL 1.0 M solution inhexanes, 2.5 mmol). The resulting reaction mixture was stirred at −78°C. for 1 h. The reaction was treated with aqueous potassium sodiumtartrate for 3 h and the mixture was extracted with EtOAc, washed withwater, brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The crude product was chromatographed (silica,hexanes/EtOAc) to give the desired compound as white solid (132 mg,45%). ESI-MS m/z=466.06, 468.07 [M−H]⁻.

Step 10c. To a mixture of compound from step (43 mg, 0.092 mmol) and NMO(64 mg, 0.55 mmol) in acetone (3.0 mL) at rt was added osmium tetroxide(0.58 ml 4% in water, 0.092 mmol) and the mixture was stirred at rt for16 h. It was quenched with aqueous Na₂SO₃, extracted with EtOAc, washedwith water, 3N HCl, NaHCO₃, brine, dry over Na₂SO₄, filtered,concentrated and purified by prep-HPLC (C18 column, acetonitrile/water)to give the title compound (18 mg, 37% racemic). ESI-MS m/z=578.07,580.07 [M+HCO₂]⁻.

Example 11

Step 11a. Into the solution of intermediate 2 (880 mg, 2.0 mmol) in THF(10 mL) vinylmagnesium chloride (1.6 M in THF 3.75 ml, 6.0 mmol) wasadded. It was stirred 30 minutes before aq. NH₄Cl was added. It wasextracted with EtOAc twice. The organic was washed with brine and dried(Na₂SO₄). After being concentrated to 10 mL, the mixture was filteredunder vacuum to provide the desired product (616 mg, 66%). ESI-MSm/z=466.08, 468.08 [M−H]−.

Step 11b. Into the solution of step 11a (94 mg, 0.2 mmol) in THF (2 mL)m-CPBA (77 w %, 224 mg, 1.0 mmol) was added and stirred at rt o/n. Afterquenched with aq. Na₂SO₃ and aq. NaHCO₃, it was extracted with EtOAc,dried and concentrated. The crude was chromatographed (silica, ethylacetate/hexanes) to give the desired compounds (75 mg, 73% yield) as awhite solid. ESI-MS m/z=514.08, 516.08 [M−H]−.

Step 11c. Into the solution of step 11b (75 mg, 0.14 mmol) in DMF (1 mL)NaN₃ (29 mg, 0.44 mmol), NH₄Cl (8 mg, 1.5 mmol) was added and stirred at55° C. o/n. After cooled, it was diluted with EtOAc and was filtered.After concentrated, was purified by prep-HPLC (C18 column,acetonitrile/water) eluent to give title compound (13.5 mg, 38%,racemic) as a white solid. ESI-MS m/z=557.04, 559.04 [M−H]−.

Example 14

To a solution of Intermediate 3 (50 mg, 0.10 mmol) and(S)-tetrahydrofuran-2-carboxylic acid (14.43 μl, 0.149 mmol) in DMF (1ml) was added EDC (38 mg, 0.20 mmol) and DMAP (36 mg, 0.30 mmol). Thereaction was stirred at rt for 2 h. The reaction was extracted withEtOAc, washed with water and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated. The crude product waschromatographed (silica, hexane/acetone) to give the title compound aswhite solid (14 mg, 23%, single enantiomer). ESI-MS m/z=599.125, 601.122[M−H]⁻.

Example 18

Into the solution of Intermediate 3 (75 mg, 0.15 mmol) and DIPEA (52.1μl, 0.298 mmol) and cyclohex-3-ene-1-carboxylic acid (18.8 mg, 0.15mmol) in DMF (1 mL) at rt was added HATU (68.0 mg, 0.18 mmol) andstirred at rt for 4 days. it was purified by prep-HPLC (C-18,Acetonitrile/water) to afford the title compound as a white solid (65mg, 71%). ESI-MS m/z=609.14, 611.14 [M−H]⁻.

Example 19

A mixture of compound from compound from example 18 (40 mg, 0.065 mmol)and NMO (23 mg, 0.196 mmol) in acetone/water (2.0/0.2 mL) at rt wastreated with osmium tetroxide (0.042 ml 4% in water, 0.0065 mmol) at rtfor 16 h. It was quenched with aqueous Na₂SO₃, extracted with EtOAc,washed with water, 3N HCl, NaHCO₃, brine, dry over Na₂SO₄, filtered,concentrated and purified by prep-HPLC (C18 column, acetonitrile/water)to give the title compound (26 mg, 61%, single isomer, stereochemistrynot determined). ESI-MS m/z=643.15, 645.15[M−H]⁻.

Example 20

Step 20a. To a suspension of (methoxymethyl)triphenylphosphoniumchloride (3.43 g, 10 mmol) THF (16 mL) at 0° C. was added t-BuOK (1.68g, 15 mmol). The resulting mixture was stirred at rt for 30 mins. Asolution of intermediate 2 (2.2 g, 5.0 mmol) in THF (4.0 mL) was addedand stirred at rt for 20 h. It was quenched with aqueous NH₄Cl and themixture was extracted with EtOAc, washed with water, brine. The organiclayer was dried (Na₂SO₄), filtered and concentrated. The crude productwas chromatographed (silica, hexanes/EtOAc) to give the desired compoundas a white solid (2.08 g, 89%). ESI-MS m/z=466.13, 468.13 [M−H]⁻.

Step 20b. Into a solution of the compound from step 20a (1.1 g, 2.35mmol) in THF (10 mL) at rt was added conc. HCl (1.5 mL) and stirred atrt for 2 h. It was concentrated under vacuum to remove majority of THFand the residue was extracted with EtOAc. The organic phase was washedwith water, 10% K₂CO₃, brine, dried over Na₂SO₄, filtered, concentratedto give desired compound (0.95 g, 89%). ESI-MS m/z=452.07, 454.07[M−H]⁻.

Step 20c. To a solution of compound from step 20b (0.27 g, 0.59 mmol) inTHF (6.0 mL) at 0° C. was added vinyl magnesium bromide (2.37 mL 1M inTHF, 2.37 mmol). The resulting reaction mixture was stirred at 0° C. for1 h. The reaction was quenched with aqueous NH₄Cl and the mixture wasextracted with EtOAc, washed with water, brine. The organic layer wasdried (Na₂SO₄), filtered and concentrated. The crude product waschromatographed (silica, hexanes/EtOAc) to give the desired compound asmixture of diasteromers (50 mg, 17%). ESI-MS m/z=480.08, 482.08 [M−H]⁻.

Step 20d. To a mixture of compound from step 20c (50 mg, 0.104 mmol) andNMO (73 mg, 0.62 mmol) in acetone (3.0 mL) at rt was added osmiumtetroxide (0.66 ml 4% in water, 0.104 mmol) and the mixture was stirredat rt for 16 h. It was quenched with aqueous Na₂SO₃, extracted withEtOAc, washed with water, 3N HCl, NaHCO₃, brine, dry over Na₂SO₄,filtered, concentrated and purified by prep-HPLC using a C18 column andacetonitrile/water as eluent to give title compound as mixture ofdiasteromers (21 mg, 37%). ESI-MS m/z=546.06, 548.06[M−H]⁻.

Example 21

Step 21a. To a clear solution of 2-methylbut-3-yn-2-ol (0.115 g, 1.364mmol) in THF (5 ml) at −78° C. was added BuLi (2.6 M in hexanes, 1.091ml, 2.73 mmol) dropwise. The resulting clear solution was stirred at−78° C. for 1 h. A solution of Intermediate 2 (0.150 g, 0.341 mmol) inTHF (1 ml) was added at −78° C. The mixture was stirred at −78° C. for 1h before being allowed to warm up to rt and stirred at rt for 30 min.Saturated NH₄Cl solution was added to quench the reaction. The mixturewas diluted with EtOAc and water. The organic layer was washed withbrine (*2), dried over Na₂SO₄ (s), filtered and concentrated. Theresidue was purified by column chromatography (silica, hexanes/EtOAc) toafford the desired product as a yellow solid (0.152 g, 85%). ESI-MSm/z=522.11, 524.11 [M−H]⁻. Step 21b. To a solution of the compound fromstep 21a (140 mg, 0.267 mmol) in ethyl acetate (12 ml) at rt was addedLindlar catalyst (114 mg, 0.053 mmol). The suspension was stirred at rtwith a H₂ balloon overnight. LC-MS showed ˜20% conversion. The mixturewas filtered through a short pad of celite. The filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/acetone) to afford the desired product as a white solid (23.5mg, 17%). ESI-MS m/z=524.11, 526.11 [M−H]⁻.

Step 21c. To a clear solution of the compound from step 21b (23.5 mg,0.045 mmol) in THF (2.80 ml) and water (0.200 ml) at rt was added NMO(26.2 mg, 0.223 mmol), followed by osmium tetroxide (4% in water, 0.057ml, 8.94 μmol). The solution was stirred at rt over the weekend beforebeing stirred at 55° C. for 2 overnights. More osmium tetroxide (4% inwater, 0.057 ml, 8.94 μmol) was added. The mixture was stirred at 55° C.overnight before being quenched with saturated Na₂S₂O₃ solution anddiluted with THF. The organic layer was washed with brine (*2), driedover Na₂SO₄ (s), filtered and concentrated. The residue was dissolved inDMSO (2 ml) and purified by HPLC (40˜90% ACN in water) to afford thetitle compound as a white solid (3.5 mg, 14%). ESI-MS m/z=556.12, 558.11[M−H]⁻.

Example 22

The title compound (44 mg, 84%) was prepared by following the proceduredescribed in Example 14 from intermediate 3 andcyclopent-3-ene-1-carboxylic acid. ESI-MS m/z=641.13, 643.13 (M+HCO₂)⁻.

Example 26

Step 26a. The desired compound was prepared from the compound of example11 following a procedure similar to that described in step Int 3d,ESI-MS m/z=531.09, 533.09 [M−H]⁻. Step 26b. A solution of compound fromstep 26a (50 mg, 0.091 mmol) and DMAP (60 mg, 0.49 mmol) in THF-water(1.0/0.1 ml) at rt was treated with MsCl (38 mg, 0.33 mmol) at rt for 1h. It was concentrated under vacuum and purified by prep-HPLC (C18,acetonitrile/water) to give the title compound (13 mg, 23%). ESI-MSm/z=609.07, 611.07 [M−H]⁻.

Example 27

Step 27a. The desired compound was prepared using a procedure similar tothat described in Example 14 from intermediate 3 and(tert-butoxycarbonyl)-L-asparagine ESI-MS. m/z=715.18, 717.18 [M−H]⁻.

Step 27b. The compound from Step 27a was treated with HCl (4 M indioxane) for two hours at rt. It was concentrated to give the titlecompound as white solid as HCl salt. ESI-MS m/z=615.12, 617.12[M−H−56]⁻.

Example 28

Step 28a Adonitol (1.0 g, 6.57 mmol) and pyridine hydrochloride (1.215g, 10.52 mmol) were mixed neat and heated to 150° C. for 4 h. The crudeproduct was chromatographed (silica, EtOAc/MeOH) to give the desiredcompound as colorless gum (882 mg, 100%).

Step 28b. To a solution compound from step 28a and 2,2-dimethoxypropane(3.23 ml, 26.3 mmol) in Acetone (26.303 ml) was added PTSA (250 mg,1.315 mmol) then stirred at rt for 30 minutes. The reaction was quenchedwith aqueous NaHCO₃ and the mixture was extracted with EtOAc, washedwith water and brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The crude product was chromatographed (silica,dichloromethane/MeOH) to give the desired compound as colorless oil (852mg, 74%).

Step 28c. To a solution of compound from Step 28b (327 mg, 1.88 mmol) inacetonitrile (2 ml) and water (2 ml) was added TEMPO (59 mg, 0.375 mmol)and iodobenzene diacetate (1.21 g, 3.75 mmol). The reaction was stirredat rt for 1 h. The reaction was extracted with EtOAc, washed with waterand brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The crude acid was used without further purification (454mg, 50% purity, 64%).

Step 28d. To a solution of Intermediate 3 (150 mg, 0.30 mmol) andcompound from step 28c (168 mg, 0.447 mmol, 50% purity) in DMF (3 ml)was added EDC (114 mg, 0.60 mmol) and DMAP (109 mg, 0.90 mmol). Thereaction was stirred at rt for 2 h. The reaction was extracted withEtOAc, washed with water and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated. The crude product waschromatographed (silica, hexane/acetone) to give the title compound aswhite solid (117 mg, 58%). ESI-MS m/z=717.153, 719.151 [M+CO₂H]⁻.

Example 29

To a solution of compound from example 28 (115 mg, 0.171 mmol) in THF (5ml) and methanol (10 ml) was added HCl (4 ml, 2M aq, 8 mmol). Thereaction was heated to 60° C. for 1 h. The reaction was extracted withEtOAc, washed with NaHCO₃, water, and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated. The crude product waschromatographed (silica, hexane/acetone) to give the title compound aswhite solid (76 mg, 70%). ESI-MS m/z=677.119, 679.117 [M+CO₂H]⁻.

Example 32

Step 32a. To solution of Intermediate 2 (3.20 g, 7.27 mmol) andtert-butyl((1-methoxyvinyl)-oxy)dimethylsilane (1.905 ml, 8.73 mmol) inTHF (36 ml) at −78° C. was added BF₃ diethyletherate (1.11 ml, 8.73mmol). Stir for 1 h at −78° C. then warm to rt over 1 h. The reactionwas quenched with NaHCO₃ (aq). The crude was extracted with EtOAc,washed with water and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated. The crude product was chromatographed(silica, hexane/EtOAc) to give the desired compound as white solid(2.976 g, 80%). ESI-MS m/z=511.8, 513.8 [M−H]⁻.

Step 32b. To a solution of material from step 32a (2.976 g, 5.79 mmol)in NMP (29 ml) was added m-CPBA (3.89 g, 17.37 mmol, 77%). The reactionwas stirred at rt for 18 h. The reaction was extracted with EtOAc,washed with water and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated. The residue was triturated with methanol andfiltered to give the title compound as a white solid (2.50 g, 4.58mmol). ESI-MS m/z=544.076, 546.074 [M−H]⁻.

Example 33

To solution of the compound of example 32 (2.50 g, 4.58 mmol) in THF (27ml) and methanol (18 ml) was added LiOH (9.16 ml, 18.32 mmol, 2M aq). Itwas stirred at rt for 6 h. The reaction was acidified to pH 3 with HCl(2M, aq). The crude was extracted with EtOAc, washed with brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated to give thetitle compound (2.40 g, 99%). ESI-MS m/z=498.068, 500.066 [M−H]⁻.

Example 34

Step 34a. To a solution of compound from intermediate 2 (1.76 g, 4.0mmol) and trimethyl-sulfoxonium iodide (1.76 g, 8.0 mmol) in DMSO (20mL) at 0° C. was added t-BuOK (1.12 g, 10 mmol). The resulting reactionmixture was stirred at rt for 1 h. The reaction was quenched withaqueous NH₄Cl and the mixture was extracted with EtOAc, washed withwater, brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The crude product was chromatographed (silica,hexanes/EtOAc) to give the desired compound as white solid (1.36 g,75%). ESI-MS m/z=452.07, 454.07 [M−H]⁻.

Step 34b. To a mixture of compound from step 34a (0.12 g, 0.264 mmol)and cyclopent-3-en-1-ol (0.523 mL, 6.61 mmol) was added potassiumtert-butoxide (297 mg, 2.64 mmol) at rt and heated at 80° C. for 1 hthen 50° C. for 16 h. The reaction was quenched with aqueous NH₄Cl andthe mixture was extracted with EtOAc, washed with water, brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated. The crudeproduct was chromatographed (silica, hexanes/EtOAc) to give the desiredcompound (82 mg, 57%). ESI-MS m/z=536.11, 538.11 [M−H]⁻.

Step 34c. To a mixture of compound from step 34b (50 mg, 0.093 mmol) andNMO (65.3 mg, 0.558 mmol) in acetone (2.0 mL) at rt was added osmiumtetroxide (0.29 ml 4% in water, 0.046 mmol) and the mixture was stirredat rt for 2 days. It was quenched with aqueous Na₂SO₃, extracted withEtOAc, washed with water, 3N HCl, NaHCO₃, brine, dry over Na₂SO₄,filtered, concentrated and purified by prep-HPLC using a C18 column andacetonitrile/water as eluent to give title compound which structure wastentatively assigned (11 mg, 19%). ESI-MS m/z=602.12, 604.12 [M−H]⁻.

Example 35

The title compound (12 mg, 21%) was isolated from example 34. ESI-MSm/z=602.12, 604.12 [M−H]⁻.

Example 36

Step 36a. To a suspension of NaH (160 mg 60%, 4.00 mmol) in DMF (5.0 mL)at 0° C. was added crotyl alcohol (341 μl, 4.00 mmol) and stirred for 30mina at rt. The compound from step 34a (182 mg, 0.40 mmol) was added andstirred at rt for 16 h. It was quenched with aqueous NH₄Cl, extractedwith EtOAc, washed with water, brine, dry over Na₂SO₄. filtered,concentrated, and chromatographed (silica, hexanes/EtOAc) to givedesired product (195 mg, 93%). ESI-MS m/z 524.11, 526.11 [M−H]⁻.

Step 36b. To a mixture of compound from step 36a (190 mg, 0.36 mmol) andNMO (254 mg, 2.17 mmol) in acetone (2.5 mL) at rt was added osmiumtetroxide (1.15 ml 4% in water, 0.181 mmol) and the mixture was stirredat rt for 2 days. It was quenched with aqueous Na₂SO₃, extracted withEtOAc, washed with water, 3N HCl, NaHCO₃, brine, dry over Na₂SO₄,filtered, concentrated and purified by prep-HPLC using a C18 column andacetonitrile/water as eluent to give title compound which structure wastentatively assigned (36 mg, 17%). ESI-MS m/z=590.11, 592.11 [M−H]⁻.

Example 37

Step 37a. To a solution of the compound from Step Int 2g (1.9 g, 4.30mmol) in NMP (12 mL) was added m-CPBA (2.89 g, 12.90 mmol) at rt. Themixture was stirred at rt overnight. It was quenched with aqueousNa₂S₂O₃ and aqueous NaHCO₃ solution with a few drops of triethylamine.The mixture was extracted with EtOAc. The organic layer was washed withwater, brine, dried over Na₂SO₄, filtered and concentrated. The residualsolid was recrystallized from MeOH to afford the desired product as awhite solid (1.8 g, 88%). ESI-MS m/z=472.06, 474.06 [M−H]⁻.

Step 37b. To a solution of the compound from step 37a (1.8 g, 3.8 mmol)in DMSO (10 mL) at rt was added MX (4.3 g, 15.3 mmol). The mixture wasstirred at 45° C. for 20 h. Aqueous Na₂S₂O₃ and aqueous NaHCO₃ solutionwith a few drops of Et₃N were added. The mixture was stirred at rt for 1h. It was extracted with EtOAc. The organic layer was washed with water,brine, dried over Na₂SO₄, filtered and concentrated to give the desiredcompound (1.65 g, 92%). ESI-MS m/z=470.04, 472.04 [M−H]⁻.

Step 37c. To a solution of the compound from step 37b (104 mg, 0.220mmol) in THF (2 mL) at 5-10° C. was added methylmagnesium bromide (3 Min ether, 367 μl, 1.102 mmol) dropwise. More THF (2.5 mL) was added andthe mixture was stirred at rt for 1 h. It was diluted with EtOAc, washedwith water, aqueous Na₂SO₃ and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated. The crude product was purified byPrep-TLC (silica, hexanes/EtOAc) to give the desired compound (85 mg,79%). ESI-MS m/z=486.08, 488.08 [M−H]⁻.

Step 37d. To a clear solution of the compound from step 37c (30.0 mg,0.061 mmol) in THF/MeOH (1/1, 2.0 ml) rt was added 10% Pd/C (6.5 mg,6.15 μmol) in one portion. The suspension was purged with H₂ 3 times andthen stirred at rt with a H₂ balloon overnight. The suspension was thenstirred at rt under H₂ (60 psi) for 4 h. More 10% Pd/C (13.0 mg, 12.3μmol) was added. The suspension was purged with H₂ 3 times and thenstirred at rt under H₂ (˜15 psi) over the weekend. The mixture wasfiltered through a short pad of celite. The filtrate was freed ofvolatiles. The solid residue was triturated with DCM to afford the titlecompound as a white solid (20.0 mg, 72%). ESI-MS m/z=452.11, 453.11[M−H]⁻.

Example 38

Step 38a. A solution of the compound from Step Int 3a (214 mg, 0.47mmol) in THF/water (3.0/1.0 mL) at rt was treated with TFA (0.40 mL) atrt for 6 h. It was concentrated under vacuum to remove majority of THF.The residue was extracted with EtOAc. The organic phase was washed withwater, 10% K₂CO₃, brine, dried over Na₂SO₄, filtered and concentrated togive the desired compound (0.20 g, 90%). ESI-MS m/z=470.08, 472.08[M−H]⁻.

Step 38b. To a solution of the compound from step 38a (0.340 g, 0.720mmol) in DMSO (6 ml) at rt was added IBX (0.303 g, 1.081 mmol). Theresulting milky mixture was stirred at rt for 2 h. The mixture wasdiluted with EtOAc and water. The organic layer was washed with brine(*2), dried over Na₂SO₄ (s), filtered and concentrated. The residue wasdried under vacuum to afford the desired product as a white solid (0.324g, 96%). ESI-MS m/z=468.05, 470.05 [M−H]⁻.

Step 38c. To a suspension of the compound from step 38b (0.324 g, 0.690mmol) in t-BuOH (6.0 ml) and water (2.0 ml) at rt was added potassiumphosphate, monobasic (0.657 g, 4.83 mmol), followed by 2-methyl-2-butene(1.826 ml, 17.24 mmol). Sodium chlorite (80%, 0.702 g, 6.21 mmol) wasadded to the suspension in one portion. The resulting clear solution wasstirred at rt for 1 h. It was diluted with MTBE and 1.0 M NaOH (8 mL).The organic layer was diluted with EtOAc, washed with 0.5 M HCl aq (*1),and then brine (*1). The organics were dried over Na₂SO₄ (s), filteredand concentrated. The residue was dried under vacuum to afford thedesired product as a white solid (0.306 g, 91%). ESI-MS m/z=484.05,486.05 [M−H]⁻.

Step 38d. To a suspension of the compound from step 38c (50.0 mg, 0.103mmol), but-2-en-1-amine hydrochloride (12.18 mg, 0.113 mmol) and DIPEA(0.054 ml, 0.309 mmol) in acetonitrile (3 ml) at rt was added HATU (47.0mg, 0.123 mmol) in one portion. The resulting slightly milky solutionwas stirred at rt overnight. More DIPEA (0.054 ml, 0.309 mmol) and HATU(47.0 mg, 0.123 mmol) were added. The resulting solution was stirred atrt for 4 h and then at 55° C. for 2 h. The mixture was freed ofvolatiles. The residue was purified by column chromatography (silica,hexanes/EtOAc) to afford the desired product as a white solid (7.0 mg,12%). ESI-MS m/z=583.11, 585.11 [M−H]⁻.

Step 38e. To a clear solution of the compound from 38d (7.0 mg, 0.013mmol) in THF (2.0 ml) and water (0.14 ml) at rt was added NMO (7.61 mg,0.065 mmol), followed by osmium tetroxide (0.083 ml, 0.013 mmol). Thesolution was stirred at 50° C. overnight. The mixture was quenched withsaturated Na₂S₂O₃ solution and diluted with THF. The organic layer waswashed with brine (*2), dried over Na₂SO₄ (s), filtered andconcentrated. The residue was dissolved in DMSO (1 ml) and purified byHPLC (40˜90% ACN in water) to afford the title compound as a white solid(3.0 mg, 38%, racemic mixture of diastereomers). ESI-MS m/z=649.13,651.13 [M+HCO₂]⁻.

Example 42

Step 42a. To a solution of the compound from Step 82a (173 mg, 0.37mmol) in CH₂Cl₂ (3.7 mL) at rt was added (Z)-but-2-ene-1,4-diyldiacetate (234 μl, 1.479 mmol) and Grubbs-Hoveyda Second generationcatalyst (23.1 mg, 0.037 mmol), then the mixture was degased and keptunder reflux for 24 h. The mixture was concentrated, and the residue waschromatographed (silica, hexanes/EtOAc) to give the desired compound aswhite solid (160 mg, 80%). ESI-MS m/z=584.10, 586.10 (M+HCO₂)⁻.

Step 42b. To a solution of the compound from Step 42a (20.5 mg, 0.038mmol) in MeOH (1.3 mL) at rt was added potassium carbonate (10.5 mg,0.076 mmol), then the mixture was kept at rt for 1 h. The reactionmixture was diluted with water and extracted with CH₂Cl₂, the organicphases were dried over Na₂SO₄, concentrated to give the desire product(19 mg) without further purification. ESI-MS m/z=542.10, 544.10(M+HCO₂)⁻.

Step 42c. To a solution of the compound from Step 42b (18.9 mg, 0.038mmol) in Acetone/H₂O (0.8 mL, 4:1) was added NMO (26.7 mg, 0.228 mmol)and Osmium tetroxide (298 μl, 0.038 mmol). The mixture was kept at 50°C. for 2 days. It was quenched with aqueous Na₂S₂O₃, extracted withEtOAc, washed with water, brine, dry over Na₂SO₄, filtered, concentratedand purified by prep-HPLC using a C18 column and acetonitrile/water aseluent to give the title compound (3.9 mg, 18%). ESI-MS m/z=608.10,610.10 (M+HCO₂)⁻.

Example 51

Step 51a. To a clear solution of1-methoxy-4-((prop-2-yn-1-yloxy)methyl)benzene (801 mg, 4.55 mmol) inTHF (15 ml) at −78° C. was added BuLi (2.6 M in hexanes, 1.819 ml, 4.55mmol) dropwise. The resulting clear solution was stirred at −78° C. for0.5 h. A solution of Intermediate 2 (500 mg, 1.137 mmol) in THF (3 ml)was added at −78° C. dropwise. The mixture was stirred at −78° C. for 1h before being quenched with saturated NH₄Cl solution. It was allowed towarm up to rt and diluted with EtOAc and water. The organic layer waswashed with brine (*1), dried over Na₂SO₄ (s), filtered andconcentrated. The residue was purified by column chromatography (silica,hexanes/EtOAc) to afford the desired product as a white solid (0.440 g,63%). ESI-MS m/z=614.14, 616.14 [M−H]⁻.

Step 51b. To a solution of the compound from step 51a (0.140 g, 0.227mmol) in ethyl acetate (10 ml) at rt was added Lindlar catalyst (0.097g, 0.045 mmol). The suspension was stirred at rt with a H₂ balloon for 2h. The mixture was filtered through a short pad of celite. The filtratewas concentrated. The residue was purified by column chromatography(silica, hexanes/EtOAc) to afford the desired product as a white solid(96.0 mg, 68%). ESI-MS m/z=616.15, 618.15 [M−H]⁻.

Step 51c. To a clear solution of the compound from step 51c (46.0 mg,0.074 mmol) in DCM (2 ml) at rt was added pH 7 buffer (0.4 ml), followedby DDQ (33.8 mg, 0.149 mmol). The biphasic mixture was stirred at rt for3 h. It was quenched with saturated NaHCO₃ solution and diluted withDCM. The organic layer was dried over Na₂SO₄ (s), filtered andconcentrated. The residue was purified by chromatography (silica,hexanes/EtOAc) to afford the desired product as a white solid (20.2 mg,54%). ESI-MS m/z=496.09, 498.09 [M−H]⁻.

Step 51d. To a clear solution of the compound from step 51c (45.6 mg,0.092 mmol) in THF (5.60 ml) and water (0.56 ml) at rt was added NMO(53.6 mg, 0.458 mmol), followed by osmium tetroxide in t-butanol (2.5%,0.186 ml, 0.018 mmol). The solution was stirred at rt for 4 h and thenat 50° C. for 2 overnights. The mixture was quenched with saturatedNa₂S₂O₃ solution and diluted with THF. The organic layer was washed withbrine (*2), dried over Na₂SO₄ (s), filtered and concentrated. Theresidue was dissolved in DMSO (2 ml) and purified by HPLC (30˜90% ACN inwater) to afford the title compound as a white solid (15.0 mg, 29%).ESI-MS m/z=608.09, 610.08 [M+HCO₂]⁻.

Example 52

To solution of compound from Example 33 (50 mg, 0.094 mmol),3-methylbut-2-en-1-amide hydrochloride (12.6 mg, 0.103 mmol), and DIPEA(0.5 ml, 0.282 mmol) in DMF (0.9 ml) was added a solution of HATU (54mg, 0.141 mmol) in DMF (0.5 ml). Stir 2 h at rt. The crude reactionmixture was chromatographed (silica, hexane/acetone) to give the titlecompound as white solid (40 mg, 71%). ESI-MS m/z=596.8, 598.8 [M−H]⁻.

Example 56

To a solution of Example 52 (40 mg, 0.067 mmol) in acetone (5 ml) wasadded OsO₄ (0.085 ml, 4% w/w water, 0.013 mmol) and NMO (19.6 mg, 0.167mmol). It was stirred for 48 h at rt then evaporated onto silica. Theresidue was chromatographed (silica, hexane/acetone) to give the titlecompound as white solid (18 mg, 43%). ESI-MS m/z=630.8, 632.8 [M−H]⁻.

Example 61

Step 61a. To a mixture of compound from example 34 (0.030 g, 0.050 mmol)and sodium bicarbonate (8.4 mg, 0.10 mmol) in THF-water (1.5/0.5 mL) wasadded sodium periodate (0.032 g, 0.150 mmol) and stirred at rt 16 h. Itwas extracted with EtOAC, washed with water, brine, dry over Na₂SO₄,filtered, concentrated and used in next step without furtherpurification. ESI-MS m/z=600.10, 602.10 [M−H]⁻.

Step 61b. To a solution of compound from step 61a (30 mg, 0.050 mmol) inTHF-MeOH (1.5/0.5 mL) was added NaBH₄ (7.57 mg, 0.20 mmol) at 0° C. thenstirred at 0° C. for 30 mins. it was quenched with aqueous NH₄Cl,extracted with EtOAc, washed with water, brine, dry over Na₂SO₄,filtered, concentrated and purified by prep-HPLC using a C18 column andacetonitrile/water as eluent to give title compound (7.6 mg, 25%).ESI-MS m/z=604.13, 606.13 [M−H]⁻.

Example 64

Step 64a. To a solution of intermediate 5 (250 mg, 0.50 mmol) in THF (5ml) in an ice-water bath was added vinylmagnesium chloride in THF (1.6M, 1.25 mL, 2.0 mmol) and stirred at rt for 1 h before it was quenchedwith aq. NH₄Cl. It was extracted with EtOAc and washed with brine. Afterdried (Na₂SO₄), it was concentrated to give the crude desired compoundwhich was used in the next step without further purification. ESI-MSm/z=528.07, 530.07 [M−H]⁻.

Step 64b. To a solution of crude compound of step 64a (0.3 mmol at most)in acetone (5 ml) and water (1 mL), NMO (67 mg, 0.57 mmol) and OsO₄ (4%in water, 0.12 mL, 0.02 mmol) was added and stirred at rt for 2 daysafter quenched with aq. Na₂S₂O₃, it was extracted with EtOAc beforebeing dried and concentrated. The crude was chromatographed (silica,acetone/hexanes) to give the title compounds as a mixture of two pair ofracemic products (122 mg, 57%, white solid). ESI-MS m/z=562.08, 564.08[M−H]⁻.

Example 70

Step 70a. To a solution of Intermediate 3 (119 mg, 0.237 mmol),Boc-(L)-alanine (49 mg, 0.260 mmol) and DIPEA (0.124 ml, 0.71 mmol) inDMF (2.4 ml) was added HATU (135 mg, 0.355 mmol). The reaction wasstirred at rt for 3 h. The reaction was extracted with EtOAc, washedwith water and brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The crude product was chromatographed (silica,hexane/acetone) to give the desired product as white solid (54 mg, 34%).

Step 70b. To a solution of compound from step 70a (54 mg, 0.08 mmol) inTHF (2 ml) was added HCl (2 ml, 8 mmol, 4M in dioxane). The reaction wasstirred for 2 h then evaporated to give crude product used withoutfurther purification.

Step 70c. To a solution of compound from step 70b (23 mg, 0.04 mmol) andDIPEA (0.017 ml, 0.1 mmol) in DMF was added isopropyl chloroformate(0.048 ml, 0.048 mmol, 1M toluene). Stir 15 minutes at rt. The crudereaction mixture was chromatographed (prep-HPLC, acetonitrile/water) togive the title compound as white solid (3.8 mg, 14%). ESI-MS m/z=660.0,662.0 [M+H]⁺.

Example 74

To a solution of compound from example 8 (62 mg, 0.092 mmol) in DMSO(0.6 mL) at rt was added IBX (38.6 mg, 0.138 mmol) and stirred at 45° C.for 16 h. It was quenched with MeOH and purified by prep-HPLC using aC18 column and acetonitrile/water as eluent to give title compound (11mg, 18%). ESI-MS m/z=670.13, 672.13 [M−H]⁻.

Example 76

Step 76. To a solution of Intermediate 3 (95.0 mg, 0.189 mmol) and(2S,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid(43.7 mg, 0.189 mmol) in DMF (3 ml) at rt was added DIPEA (0.099 ml,0.567 mmol), followed by HATU (108 mg, 0.283 mmol). The resulting clearsolution was stirred at rt for 1 h. The mixture was freed of volatiles.The residue was dissolved in DCM with some THF and purified by columnchromatography (silica, DCM/MeOH) to afford the title compound as acolorless sticky oil (128 mg, 95%). ESI-MS m/z=760.20, 762.20 [M+HCO2]⁻.

Example 78

Step 78a. To a solution of compound from example 76 (0.064 g, 0.090mmol) in THF (2 ml) at rt was added HCl (4 M in 1,4-dioxane, 0.900 ml,3.60 mmol). The resulting clear solution was stirred at rt for 3 h. Itturned into a suspension. The mixture was concentrated. The residualsolid was used directly for next step. ESI-MS m/z=660.15, 662.15[M+HCO₂]⁻.

Step 78b. To a solution of the compound from step 78a (0.090 mmol) inDMF (2.0 ml) at rt was added DIPEA (0.157 ml, 0.900 mmol), followed by asolution of methyl chloroformate (6.97 μl, 0.090 mmol) in DMF (0.1 ml).The resulting yellow solution was stirred at rt for 1 h before beingfreed of volatiles. The residue was dissolved in DMSO (2 ml) andpurified by HPLC (40˜90% ACN in water) to afford the title compound as awhite solid (20.0 mg, 33% over 2 steps). ESI-MS m/z=718.16, 720.16[M+HCO₂]⁻.

Example 82

Step 82a. To a solution of the compound of step 150d (210 mg, 0.50 mmol)in THF (5 ml) in an ice-water bath was added vinylmagnesium chloride inTHF (1.6 M, 0.94 mL, 1.5 mmol). It was stirred at rt for 1 h before itwas quenched with aq. NH₄Cl. It was extracted with EtOAc and washed withbrine. After drying (Na₂SO₄), it was concentrated and the residue waschromatographed (silica, EtOAc/hexanes) to give the desired compound(201 mg, 94%) as a white solid. ESI-MS m/z=448.08, 450.08 [M−H]⁻.

Step 82b. To a solution of the compound of step 82a (152 mg, 0.34 mmol)in acetone (1 ml) and water (0.2 mL), NMO (79 mg, 0.68 mmol) and OsO₄(2.5% in t-BuOH, 0.12 mL, 0.007 mmol) was added. It was stirred at rto/n before being quenched with aq. Na₂S₂O₃. It was extracted with EtOAc,dried and concentrated. The crude was crystallized from MeOH to give thetitle compound (141 mg, 84%, racemic) as a white solid. ESI-MSm/z=514.08, 516.08 [M−H]−.

Example 106

The title compound (single enantiomer) was isolated from the preparationof the compound of example 13. ESI-MS m/z=645.11, 647.11 [M−H]⁻.

Example 108

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 4 via SFC chromatography.

Example 109

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 5 via SFC chromatography.

Example 120

To a solution of compound from example 119 (50 mg, 0.083 mmol) in THF (1ml) and water (0.67 ml) was added LiOH (0.33 ml, 0.67 mmol, 2 M aq) atrt. The reaction was stirred for 1 h, then acidified to pH 3 with 2MHCl. The reaction was extracted with EtOAc, washed with water and brine.The organic layer was dried (Na₂SO₄), filtered and concentrated to givethe title compound as a white solid (40 mg, 82%). ESI-MS m/z=586.8,588.8 [M−H]⁻.

Example 121

Step 121a. To a solution of compound from step 34a (170 mg, 0.375 mmol)and 1,3-dimethoxypropan-2-ol (900 mg, 7.49 mmol) in THF (2 mL) was addedpotassium 2-methylpropan-2-olate (630 mg, 5.62 mmol) at rt then themixture was stirred at 60° C. for 20 h. It was cooled to rt, quenchedwith aqueous NH₄Cl, extracted with EtOAc, washed with water, brine, dryover Na₂SO₄, filtered, concentrated and chromatographed (silica,hexanes/EtOAc) to give desired product (98 mg, 45%). ESI-MS m/z 572.15,574.15 [M−H]⁻. Step 121b. To a solution of compound from step 121a (95mg, 0.165 mmol) in NMP (1.5 mL) was added mCPBA (0.167 g 77%, 0.745mmol) and stirred at rt for 20 h. Aqueous Na₂S₂O₃, NaHCO₃ and few dropsof Et₃N was added and stirred at rt for 1 h. It was extracted withEtOAc, washed with water, brine, dry over Na₂SO₄, filtered, concentratedand purified by prep-HPLC using a C18 column and acetonitrile/water aseluent to give title compound (44 mg, 44%). ESI-MS m/z=604.14, 606.14[M−H]⁻.

Example 124

Step 124a. To a suspension of methyltriphenylphosphonium bromide (0.24g, 0.67 mmol) THF (1.0 mL) at 0° C. was added t-BuOK (0.11 g, 1.0 mmol).The resulting reaction mixture was stirred at rt for 30 mins. A solutionof compound from intermediate 2 (0.15 g, 0.34 mmol) in THF (1.0 mL) wasadded and stirred at rt for 24 h. The reaction was quenched with aqueousNH₄Cl and the mixture was extracted with EtOAc, washed with water,brine. The organic layer was dried (Na₂SO₄), filtered and concentrated.The crude product was chromatographed (silica, hexanes/EtOAc) to givethe desired compound as white solid (1.36 g, 75%). ESI-MS m/z=436.08,438.07 [M−H]⁻.

Step 124b. To a suspension of compound from step 124a (0.35 g, 0.80mmol) and NMO (0.375 g, 3.2 mmol) in acetone-water (6 mL/1 mL) at rt wasadded osmium tetroxide (1.0 ml, 0.080 mmol) and the mixture was stirredat rt for 18 h. It was quenched with aqueous Na₂SO₃, extracted withEtOAc, washed with water, 3N HCl, NaHCO₃, brine, dry over Na₂SO₄,filtered, concenrated to give a mixture of sulfone and sulfoxide.

Step 124c. To a solution of compound from step 124b (156 mg, 0.32 mmol)in DMF (1.5 mL) at 0° C. was added NaH (45 mg 60%, 1.12 mmol) and MeI(45 mg, 0.32 mmol). After 1.5 h at 0° C., the reaction was quenched withaqueous NH₄Cl solution, extracted with EtOAc and the organic layer waswashed with water and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated, purified on prep-HPLC (C-18,Acetonitrile/water) to afford the title compound as a white solid (61mg, 38%). ESI-MS m/z=500.09, 502.09 [M−H]⁻.

Step 124d. To a solution of compound from step 124c (61 mg, 0.122 mmol)in NMP (1.5 mL) was added mCPBA (0.11 g 77%, 0.49 mmol) and stirred atrt for 20 h. Aqueous Na₂S₂O₃, NaHCO₃ and few drops of Et₃N was added andstirred at rt for 1 h. It was extracted with EtOAc, washed with water,brine, dry over Na₂SO₄, filtered, and concentrated to give the titlecompound (63 mg, 100%). ESI-MS m/z=516.08, 518.08 [M−H]⁻.

Example 125

Step 125a. To a solution of compound of step int 3a (91 mg, 0.2 mmol) inDMF (1 ml), was added (S)-1-aminopropan-2-ol (45 mg, 0.6 mmol) andstirred at 90° C. for 20 hours before being cooled. It was concentratedto give the crude desired compound which was used in the next stepwithout further purification. ESI-MS m/z=527.12, 529.12 [M−H]⁻.

Step 125b. To a solution of half of the compound of step 125a (˜0.1mmol) in CH₂Cl₂ (1 ml) was added TEA (3 drops) and acetic anhydride (20mg). It was stirred 2 hours before was concentrated. NMP (1 mL) wasadded, followed by m-CPBA (13.5 mg, 6 mmol) and stirred at rt for 20hours. The crude was purified by prep-HPLC (C18, acetonitrile/water) togive title compound (18 mg, 30%, three steps). ESI-MS m/z=601.13, 603.13[M−H]⁻.

Example 130

Step 130a. To a solution of (R)-propane-1,2-diol (168 mg, 2.20 mmol) inDMF (3 mL) was added NaH (88 mg 60%, 2.20 mmol) at 0° C. and stirred atrt for 30 mins. The compound from step 34a (100 mg, 0.220 mmol) wasadded and heated at 55° C. for 20 h. It was cooled to rt, quenched withaqueous NH₄Cl, extracted with EtOAc, washed with water, brine, dry overNa₂SO₄, filtered, concentrated and chromatographed (silica,hexanes/EtOAc) to give desired product (65 mg, 56%). ESI-MS m/z 528.12,530.12 [M−H]⁻.

Step 130b. To a solution of compound from step 130a (80 mg, 0.15 mmol)in NMP (1.5 mL) was added mCPBA (0.169 g 77%, 0.75 mmol) and stirred atrt for 20 h. Aqueous Na₂S₂O₃, NaHCO₃ and few drops of Et₃N was added andstirred at rt for 1 h. It was extracted with EtOAc, washed with water,brine, dry over Na₂SO₄, filtered, concentrated and purified by prep-HPLCusing a C18 column and acetonitrile/water as eluent to give titlecompound (65 mg, 77%, single enantiomer). ESI-MS m/z=560.11, 562.11[M−H]⁻.

Example 136

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 4 via SFC chromatography. ESI-MSm/z=546.10 [M+H]⁺.

Example 137

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 5 via SFC chromatography. ESI-MSm/z=546.05[M+H]⁺.

Example 141

Step 141a. A solution of Intermediate 1 (1.23 g, 3.88 mmol),3-exo-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butylester (801 mg, 3.52 mmol) in 50 ml toluene was added2-(tributyl-15-phosphanylidene)acetonitrile (2.13 g, 8.81 mmol) thenstirred at 85° C. O/N. it was diluted with methyl tert-butyl ether,washed with 0.5 N NaOH aqueous solution, water, brine, dry over Na₂SO₄,filtered, concentrated. The residue was chromatographed (silica,hexanes/EtOAc) to give the desired compound as white solid (1.63 g,86%). ESI-MS m/z=525.12, 527.12 (M−H)⁻.

Step 141b. To the solution of the compound from Step 141a (1.31 g, 2.48mmol) in N-Methyl-2-pyrrolidinone (8.29 ml) at rt was added mCPBA (1.95g, 8.70 mmol), then the mixture was kept at rt for overnight. Thereaction was quenched with Na₂S₂O₃ aqueous solution. The mixture wasextracted with EtOAc, and the combined organic phases were dried overNa₂SO₄, filtered and concentrated. The residue was chromatographed(silica, hexanes/EtOAc) to give the desired compound as white solid(1.28 g, 92%). ESI-MS m/z=557.11, 559.11 (M−H)⁻.

Step 141c. To a solution of the compound from Step 141b (131 mg, 0.234mmol) was added 2N HCl in dioxane at rt, then the mixture was kept at rtfor 4 h. The solution was concentrated to give a white solid (106 mg,99%). ESI-MS m/z=457.06, 459.06 (M−H)⁻.

Step 141d. To a solution of the compound from Step 141c (45 mg, 0.091mmol) in DMF (1.8 mL) at rt was added iPr₂EtN (63.5 μl, 0.363 mmol),(methoxycarbonyl)-L-alanine (13.4 mg, 0.091 mmol) and HATU (51.8 mg,0.136 mmol). The mixture was kept at rt for overnight. The mixture waspartitioned between EtOAc and water. The organic phase was washed withNaHCO₃ aqueous solution, water and brine, dried over Na₂SO₄, filteredand concentrated. The residue was chromatographed (silica, CH₂Cl₂/MeOH)to give the title compound as white solid (37 mg, 69%, singleenantiomer). ESI-MS m/z=586.10, 588.10 (M−H)⁻.

Example 144

To a solution of the compound from Step 141c (49 mg, 0.099 mmol) in MeOH(0.99 mL) at rt was added (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde(19.31 mg, 0.148 mmol) and NaCNBH₄ (12.4 mg, 0.198 mmol), then themixture was kept at rt for overnight. The reaction was quenched withNH₄Cl aqueous solution at rt. The reaction mixture was partition betweenEtOAc and water, then the organic phase was washed with water and brine,dried over Na₂SO₄, filtered and concentrated. The residue waschromatographed (silica, CH₂Cl₂/MeOH) to give the title compound aswhite solid (45 mg, 79%, single enantiomer). ESI-MS m/z=571.12, 573.12(M−H)⁻.

Example 150

Step 150a. To a solution of compound from step Int 2e (246 g, 959 mmol)and pyridine (155 ml, 1.92 mol) in DCM (1 L) at 0° C. was added3-nitrobenzenesulfonyl chloride (217 g, 978 mmol). The reaction mixturewas stirred at 0° C. for 30 mins and rt for 2 days. It was quenched withwater (100 mL) and stirred at rt for 1 hr followed by extraction withMBTE (4 L). The organic layer washed with water (2λ1 L), 1N HCl (1 L),water (500 mL), sat NaHCO₃ (500 mL), and brine (500 mL), dried overNa₂SO₄, filtered through celite and concentrated to about (500 mL), thenhexanes (500 mL) was added. The mixture was concentrated under vacuum toinduce precipitation, cooled to rt and filtered, washed with coldhexanes to give desired product (321 g, 76%).

Step 150b. To a solution of compound from step 150a (108.6 g, 246 mmol),Intermediate 4 (70 g, 234 mmol) in DMF (250 mL) was added cesiumcarbonate (96 g, 295 mmol). The reaction mixture was degased and slowlyheated to 70° C. and stirred at 70° C. for 14 h. It was cooled to rt,diluted with MBTE, washed with water and brine, dried over Na₂SO₄,filtered and concentrated to give desired product (123 g, 98%) which wasused without further purification.

Step 150c. To a suspension of compound from step 150b (50 g, 93 mmol) inMeOH (1.6 L) in a cold water bath was added Con. HCl (200 mL) slowly tokeep temperature below 30° C., then stirred at rt overnight. Thereaction mixture was concentrated under vacuum to a volume of ˜700 mL,cooled to 0° C., then filtered to collect the solid, which was washedwith cold MeOH. Then mother liquor was concentrated to 300 mL, cooled to0° C., filtered to collect solid. The solid was air dried for 14 h togive desired product (36 g, 91%).

Step 150d. To a solution of compound from step 150c (36 g, 85 mmol) inDMSO (150 mL) at rt was added IBX (30.9 g, 110 mmol), then stirred at50° C. for 2 h. The mixture was poured into 1.2 L cold water, which wasextracted with EtOAc (2×500 mL). Some white solid was removed byfiltration. The EtOAc extracts were washed with saturated aq. NaHCO₃solution, brine, dried over Na₂SO₄. Filtration and concentration to ˜150mL, then cooling to 0° C. gave desired solid that was collected byfiltration. The mother liquor was concentrated to 50 mL to give thesecond crop of desired product (34.1 g, 95%).

Step 150e. To a suspension of trimethylsulfoxonium iodide (36.3 g, 165mmol) in DMF (180 ml) at 0° C. was added potassium tert-butoxide (18.51g, 165 mmol, 1.6 eq) then stirred at rt for 30 mins. A solution ofcompound from step 150d (43.5 g, 103 mmol) in DMF (120 ml) was added tothe reaction mixture via cannula (temperature below 10° C.) and stirredat rt for 16 h. The reaction mixture was poured into cold saturatedNH₄Cl (500 mL) and MBTE (1.2 L). The organic layer was washed with water(3×500 mL) and saturated NaCl (2×300 mL). The organic layer was driedwith Na₂SO₄, filtered through a silica plug, washed with MBTE andconcentrated to afford crude desired product that was used withoutfurther purification.

Step 150f. To a solution of crude material from step 150e in THF/water(220/70 mL) in an ice/water bath was added TFA (30.8 ml, 400 mmol) thenstirred at rt for 6.5 hours then cooled to 0° C. and 20 mL sat NaHCO₃was added slowly and followed by solid NaOH (16.00 g, 400 mmol). EtOAc(800 mL) and water (600 mL) was added. The organic layer was washed witha mixture solution of NaHCO₃ and brine, then brine, dried (Na₂SO₄)filtered and concentrated to about 150 mL then, 450 mL cyclohexane wasadded cooled to 0° C., filtered, wash with cyclohexane/EtOAc (3/1) togive the desired product (39 g, 83 mmol, 81% yield for 2 steps).

Step 150g. To a solution of compound from step 150f (5.75 g, 12.67 mmol)in NMP (40 ml) at 0° C. was added m-CPBA (8.52 g, 38.0 mmol, 77%) in oneportion. Stir o/n at rt. Dilute with EtOAc, wash with Na₂S₂O₃, NaHCO₃,water and brine. Dry over Na₂SO₄ filter and concentrate. Crude productwas recrystallized from MeOH. Dry at rt o/n in vacuum to give the titlecompound (4.10 g, 8.44 mmol, 66.6% yield). ESI-MS m/z=484.08, 486.08[M−H]⁻.

Example 153

A solution of the compound from Step 144a in AcOH (500 μl, 8.73 mmol)was stirred at rt overnight. The reaction mixture was concentrated, andthe residue was chromatographed (silica, CH₂Cl₂/MeOH) to give the titlecompound as white solid (17 mg, 88%, single enantiomer). ESI-MSm/z=577.10, 579.10 (M+HCO₂)⁻.

Example 156

Intermediate 3 (78 mg, 0.155 mmol) and sulfuric diamide (44.7 mg, 0.465mmol) in dioxane (0.5 mL) was stirred at 105° C. for 3 h. It was cooledto rt and purified by prep-HPLC using a C18 column andacetonitrile/water as eluent to give title compound (42 mg, 46%). ESI-MSm/z=580.06, 582.06 [M−H]⁻.

Example 163

Two enantiomers of Example 36 were separated by chiral SFC. The titlecompound (tentatively assigned) was eluted out earlier. ESI-MSm/z=590.11, 592.11 [M−H]⁻.

Example 164

Two enantiomers of Example 36 were separated by chiral SFC. The titlecompound (tentatively assigned) was eluted out later. ESI-MS m/z=590.11,592.11 [M−H]⁻.

Example 174

The title compound (single enantiomer, tentatively assigned, eluted outearlier) was isolated from the compound of example 82 via SFCchromatography. ESI-MS m/z=514.09, 516.09 [M−H]⁻.

Example 175

The title compound (single enantiomer, tentatively assigned, eluted outlater) was isolated from the compound of example 82 via SFCchromatography. ESI-MS m/z=514.09, 516.09 [M−H]⁻.

Example 180

The title compound (single enantiomer, tentatively assigned, eluted outearlier) was isolated from the compound of example 172 via SFCchromatography. ESI-MS m/z=528.10, 530.10[M−H]⁻.

Example 181

The title compound (single enantiomer, tentatively assigned, eluted outlater) was isolated from the compound of example 172 via SFCchromatography. ESI-MS m/z=528.10, 530.10[M−H]⁻.

Example 182

The title compound (single enantiomer eluted out earlier) was isolatedfrom the compound of example 173 via SFC chromatography. ESI-MSm/z=528.10, 530.10[M−H]⁻.

Example 183

The title compound (single enantiomer, eluted out later) was isolatedfrom the compound of example 173 via SFC chromatography. ESI-MSm/z=528.10, 530.10[M−H]⁻.

Example 202

Step 202a. To a solution of methyl(R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (55 mg, 0.35 mmol) in THF(1 ml), was added LDA (0.34 mmol) freshly prepared in THF at −78° C. andstirred at same temperature for 15 minutes before a solution ofintermediate 2 (100 mg, 0.23 mmol) in THF (1 mL) was added. It wasraised to 0° C. in one hour and quenched by aq. NH₄Cl. It was extractedwith EtOAc and washed with brine and dried (Na₂SO₄). After beingconcentrated, the crude was chromatographed (silica, EtOAc/hexanes) togive the desired compound (79 mg, contaminated with intermediate 2).ESI-MS m/z=598.12, 600.12[M−H]⁻. Step 125b. To a solution of compound ofstep 202a (79 mg, 0.13 mmol) in THF (2 ml), was added m-CPBA (112 mg,0.5 mmol) and stirred at rt. o/n. The crude was purified by prep-HPLC(C18, acetonitrile/water) to give title compound (13 mg, 10%, twosteps). ESI-MS m/z=630.11, 632.11 [M−H]⁻.

Example 203

To a solution of the compound of example 150 (207 mg, 0.426 mmol) inDMSO (2.1 ml) was added IBX (179 mg, 0.639 mmol). The reaction stirredat rt for 2 h. The reaction was extracted with EtOAc, washed with waterand brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The crude product was chromatographed (silica,hexane/acetone) to give the title compound as white solid (175 mg, 85%).ESI-MS m/z=481.6, 483.6 [M−H]⁻.

Example 204

To a solution of the compound of example 150 (103 mg, 0.212 mmol) in THF(2 ml) and NaHCO₃ (aq sat. 1 ml) was added NaIO₄ (140 mg, 0.655 mmol).The reaction stirred at rt for 2 h. The reaction was extracted withEtOAc, washed with water and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated. The crude product waschromatographed (silica, hexane/acetone) to give the title compound aswhite solid (60 mg, 62%). ESI-MS m/z=452.05, 454.05 [M−H]⁻.

Example 205

To a solution of the compound of example 203 (140 mg, 0.289 mmol),2-methyl-2-butene (0.77 ml, 7.23 mmol), KH₂PO₄ (276 mg, 2.025 mmol) inTHF (3 ml) and water (1 ml) was added NaClO₂ (294 mg, 2.60 mmol). Thereaction stirred at rt for 1 h. The reaction acidified to pH 4 with 1MHCl then extracted with EtOAc, washed with water and brine. The organiclayer was dried (Na₂SO₄), filtered and concentrated. The crude productwas chromatographed (silica, hexane/acetone) to give the title compoundas white solid (109 mg, 75%). ESI-MS m/z=497.7, 499.6 [M−H]⁻.

Example 206

To a solution of the compound of example 204 (22 mg, 0.048 mmol) in THF(0.5 ml) and MeOH (0.5 ml) was added NaBH₄ (9 mg, 0.244 mmol). Thereaction stirred at rt for 15 minutes. The reaction was extracted withEtOAc, washed with water and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated to give the title compound as whitesolid (21 mg, 95%, stereochemistry not determined). ESI-MS m/z=453.6,455.6 [M−H]⁻.

Example 210

To a solution of the compound from Step 11b (47 mg, 0.091 mmol) in THF(911 μl) was added 2N LiBH₄ solution (22.77 μl, 0.046 mmol) at rt, thenthe mixture was kept at rt for overnight. The reaction was quenched withNH₄Cl aqueous solution, and the mixture was extracted with EtOAc. Thecombined organic phases were washed with water and brine, dried overNa₂SO₄, filtered and concentrated. The residue was chromatographed(silica, CH₂Cl₂/MeOH) to give the title compound as white solid (14 mg,30%). ESI-MS m/z=562.09, 564.09, (M+HCO₂)⁻.

Example 272

Step 272a. To a suspension of Me₃SOI (1.98 g, 9.0 mmol.) in DMF (5.0 mL)at 0° C. was added t-BuOK (1.01 g, 9.0 mmol.) and stirred at rt for onehour. The reaction was cooled to 0° C.(1R,5S)-3-methylenebicyclo[3.2.1]octan-8-one-6,6,7,7-d4 (in DMF (2.0mL), which was prepared using procedures similar to those described instep intermediate 2a, was charged drop-wise to the reaction mixture. Thereaction was stirred for 2 hours. To the reaction mixture was added 15%NH₄Cl drop-wise and extracted with MTBE. The aqueous phase wasre-extracted by MTBE. Then all the organic phase was combined and washedwith water and brine. The organic phase was dried over Na₂SO₄, filteredand concentrated to dryness to give the desired product (0.59 g, 64%).

Step 272b. To a solution of compound from step 272a (0.59 g, 3.83 mmol)in THF/water (3.9/1.3 mL) at 0° C. was added TFA (0.589 mL, 7.65 mmol).The reaction was stirred at rt for 20 hours. The reaction was cooled to0° C. and Na₂CO₃ was added slowly and adjusted pH to 7-8. EtOAc andwater were added. The two layers were separated (brine was added toassist separation), the organic layer was washed with water and brine.The organic phase was dried over Na₂SO₄, filtered and concentrated todryness to give desired product (0.50 g, 76%).

Step 272c. To a solution of compound from step 272b (0.48 g, 2.8 mmol),imidazole (0.57 g, 8.4 mmol) in DMF (4.0 mL) was added TBSCl (0.63 g,4.2 mmol) and stirred at rt for 18 h. It was quenched by pouring intocold water. The product was extracted with hexanes. The organic phasewas washed with brine, dried over Na₂SO₄, filtered and concentrated togive crude product (0.97 g, 100%).

Step 272d. To a solution of compound from step 272c. (1.43 g, 5.0 mmol)in dioxane-water (18/6.0 mL) was added 2,6-lutidine (1.16 mL, 10 mmol.),and OsO₄ (0.78 mL, 2.5% solution in t-butanol, 0.05 mmol). The mixturewas cooled to 0° C. and NaIO₄ (3.21 g, 15 mmol) was added. Thesuspension was stirred at rt for 16 hours. Aq. Na₂S₂O₃ solution wasadded. The mixture was stirred for 1 hour and filtered through celite.The mixture was extracted with MBTE/Hexanes. The organic phase waswashed with water, 1 N HCl, Sat. NaHCO₃ and brine. The organic phase wasseparated, dried over Na₂SO₄, filtered and concentrated to give thecrude product (1.0 g, 69%).

Step 272e. To a solution of LiBD₄ (0.108 g, 4.2 mmol) was added compoundfrom step 272d (0.577 g, 2.0 mmol) in MBTE (12 mL) dropwise at 0° C. Theresulting solution was stirred for 2 hours at 0° C. The reaction wasquenched by slowly addition of aq. NH₄Cl keeping the temperature below15° C. The reaction mixture was diluted with MBTE and water. The mixturewas separated, and the organic layer was washed with brine. The mixturewas dried over Na₂SO₄, filtered and concentrated under vacuum. The crudeproduct was chromatographed (silica, hexanes/EtOAc) to give the desiredcompound as white solid (0.39, 67%).

Step 272f. To a solution of compound from step 272e (0.39 g, 1.34 mmol)and pyridine (0.216 mL, 2.68 mmol) in DCM (2 mL) at rt was added TsCl(0.306 g, 1.60 mmol) and stirred at rt for 40 h. It was quenched withH₂O and extracted with EtOAc. The mixture was washed with H₂O, 1 M HCl,Sat. NaHCO₃ and brine. The organic phase was collected, dried overNa₂SO₄, filtered and concentrated. The crude product was chromatographed(silica, hexanes/EtOAc) to give the desired compound as white solid(0.59, 99%).

Step 272g. To a solution of compound from step 272f (1.7 g, 3.81 mmol)in MeOH (22 mL) was added conc. HCl (1.0 mL) and stirred at rt for 16 h.It was diluted with EtOAc and the mixture washed with water, sat.NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was recrystallized from hexanes/MBTE to give desired product(1.1 g, 87%).

Step 272h. A solution of compound from step 272g (0.16 g, 0.48 mmol),intermediate 6 (0.12 g, 0.40 mmol) and Cs₂CO₃ (0.128 g, 0.392 mmol) inDMF (1.0 mL) was stirred at 75° C. for 16 h. It was diluted with EtOAcand the mixture washed with water, brine, dried over Na₂SO₄, filteredand concentrated. The crude product was chromatographed (silica,hexanes/EtOAc) to give the desired compound as white solid (0.162 g,88%). ESI-MS m/z=457.12, 459.12 [M−H]⁻.

Step 272i. A solution of compound from step 272h (0.16 g, 0.35 mmol) andm-CPBA (253 mg, 1.13 mmol, 77%) in NMP (2.0 mL) was stirred at rt for 24h. Aqueous Na₂S₂O₃, NaHCO₃ and few drops of Et₃N was added and stirredat rt for 1 h. It was extracted with EtOAc, washed with water, brine,dry over Na₂SO₄, filtered, recrystallized from MeOH to give titlecompound (118 mg, 68%). ESI-MS m/z=489.11, 491.11 [M−H]⁻.

Example 279

Step 279a. To a suspension of Me₃SOI (48.5 g, 220 mmol.) in DMF (120 mL)at 0° C. was added t-BuOK (24.72 g, 220 mmol) and stirred at rt for onehour. The reaction was cooled to 0° C. Intermediate 2a (20 g, 147 mmol)in DMF (80 mL) was charged drop-wise to the reaction mixture. Thereaction was stirred for 2 hours. To the reaction mixture was added 15%NH₄Cl drop-wise and extracted with MTBE. The aqueous phase wasre-extracted by MTBE. The combined organic layer was washed with waterand brine, dried over Na₂SO₄, filtered and concentrated to give thedesired product (19.9 g, 90%).

Step 279b. To a solution of compound from step 279a (20 g, 133 mmol) inTHF/water (150/50 mL) at 0° C. was added TFA (30.8 mL, 399 mmol). Thereaction was stirred at rt for 3 hours, then cooled to 0° C. and Na₂CO₃was added slowly and adjusted pH to 7-8. EtOAc and water were added. Thetwo layers were separated (brine was added to assist separation), theorganic layer was washed with water and brine, dried over Na₂SO₄,filtered and concentrated to provide desired product (17.7 g, 79%).

Step 279c. To a solution of compound from step 279b (10 g, 59.4 mmol),imidazole (10.2 g, 148 mmol) in DMF (80 mL) was added TBSCl (10.7 g,71.3 mmol) and stirred at rt for 18 h. It was quenched by pouring intocold water. The product was extracted with hexanes. The organic phasewas washed with brine, dried over Na₂SO₄, filtered and concentrated togive crude product (18.1 g, 100%).

Step 279d. To a solution of compound from step 279c. (16.8 g, 59.4 mmol)in dioxane-water (170/60 mL) was added 2,6-lutidine (13.8 mL, 119mmol.), and OsO₄ (9.3 mL 2.5% solution in t-butanol, 0.59 mmol). Themixture was cooled and NaIO₄ (37.1 g, 178.2 mmol) was added. Thesuspension was stirred at rt for 16 hours. Aq. Na₂S₂O₃ solution wasadded. The mixture was stirred for 1 hour and filtered through celite.The mixture was extracted with MBTE/Hexanes. The organic phase waswashed with water, 1 N HCl, Sat. NaHCO₃ and brine. The organic phase wasseparated, dried over Na₂SO₄, filtered and concentrated to give thecrude product (16.6 g, 94%).

Step 279f. To a solution of compound from step 279d (143 mg, 0.503 mmol)in CD₃OD (3.0 mL) was added MeONa (5.4 mg, 0.10 mmol) and the mixturewas stirred at rt for 3 h. It was concentrated and the residue wasredissolved in CD₃OD (3.0 mL) and stirred for 3 h. The same reactioncycle was repeated two more times and the solution was cooled to 0° C.and NaBD₄ (0.10 g, 2.4 mmol) was added portionwise. After 1 h, it wasquenched by slowly addition of aq. NH₄Cl. MBTE and water were added. Themixture was separated, and the organic layer was washed with brine. Themixture was dried over Na₂SO₄, filtered and concentrated under vacuum.The crude product was chromatographed (silica, hexanes/EtOAc) to givethe desired compound as white solid (0.070 g, 50%).

Step 279g. To a mixture of intermediate 6 (73 mg, 0.24 mmol) andcompounds from step 279f (71 mg, 0.24 mmol) in toluene (1.5 mL) at rtwas added cyanomethylenetributyl-phosphorane (176 mg, 0.73 mmol) andstirred at 75° C. for 16 h. The mixture was cooled to rt and waschromatographed (silica, hexanes/EtOAc) to give the desired compound aswhite solid (0.11 g, 79%). ESI-MS m/z=571.21, 573.21 [M−H]⁻.

Step 279h. To a solution of compound from step 279g (0.11 g, 0.19 mmol)in MeOH (3.0 mL) was added con. HCl (0.3 mL) and stirred at rt for 2 h.It was diluted with EtOAc and the mixture washed with water, Sat.NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was recrystallized from hexanes/MBTE to give desired product(0.083 g, 94%). ESI-MS m/z=457.12, 459.12 [M−H]⁻.

Step 279i. A solution of compound from step 279h (0.083 g, 0.18 mmol)and m-CPBA (0.14 g, 0.63 mmol, 77%) in NMP (2.0 mL) was stirred at rtfor 24 h. Aqueous Na₂S₂O₃, NaHCO₃ and few drops of Et₃N was added andstirred at rt for 1 h. It was extracted with EtOAc, washed with water,brine, dried over Na₂SO₄, filtered, concentrated purified by prep-HPLC(C18, acetonitrile/water) to give title compound (48 mg, 54%). ESI-MSm/z=489.11, 491.11 [M−H]⁻.

Example 281

Step 281a. To a solution of compound from step 150f (4.0 g, 8.11 mmol)in DMSO (22 mL) was added IBX (3.70 g, 13.22 mmol). The reaction mixturewas heated to 50° C. for 3 h. The reaction mixture was then cooled to rtand diluted with EtOAc. The reaction mixture was filtered, the soliddiscarded and the filtrate was washed with water and saturated NaCl. Theorganic layer was dried with Na₂SO₄, filtered and concentrated to affordcrude desired product that was used without further purification (3.90g, 98%).

Step 281b. To a solution of compound from step 281a (50 mg, 0.111 mmol)in THF (0.53 mL) at −78° C. was added isopropylmagnesium chloride,lithium chloride complex (237 μL, 0.243 mmol, 1.3M in THF). The reactionmixture was stirred for 30 minutes and quenched by aq. NH₄Cl. It wasextracted with EtOAc and washed with brine and dried (Na₂SO₄). Afterbeing concentrated, the crude was chromatographed (silica,EtOAc/hexanes) to give the desired compound (18 mg, 33%). ESI-MSm/z=540.14, 542.14[M+HCO₂]⁻.

Step 281c. To a solution of compound from step 281b (18 mg, 0.01 mmol)in NMP (0.5 ml), was added m-CPBA (24 mg, 0.096 mmol, 77%) and stirredat rt o/n. The reaction was extracted with EtOAc, washed with water andbrine. The organic layer was dried (Na₂SO₄), filtered and concentrated.The crude product was chromatographed (silica, hexane/acetone) to givethe title compound as white solid (14 mg, 73%). ESI-MS m/z=572.13,574.13 [M+HCO₂]⁻.

Example 283

Step 283a. To a solution of compound from step 281a (50 mg, 0.111 mmol)in THF (0.53 mL) at −78° C. was added phenylmagnesium bromide (237 μL,0.243 mmol, 1M in THF). The reaction mixture was stirred for 30 minutesand quenched by aq. NH₄Cl. It was extracted with EtOAc and washed withbrine and dried (Na₂SO₄). After being concentrated, the crude waschromatographed (silica, EtOAc/hexanes) to give the desired compound (17mg, 29%). ESI-MS m/z=574.13, 576.13[M+HCO₂]⁻.

Step 283b. To a solution of compound from step 283a (17 mg, 0.03 mmol)in NMP (0.5 ml), was added m-CPBA (22 mg, 0.096 mmol, 77%) and stirredat rt o/n. The crude was purified by prep-HPLC (C18, acetonitrile/water)to give title compound (3 mg, 17%). ESI-MS m/z=606.12, 608.12 [M+HCO₂]⁻.

Example 284

Step 284a. To a solution of 2-bromopyridine (46 μL, 0.49 mmol) in THF (1mL) at 0° C. was added isopropylmagnesium chloride, lithium chloridecomplex (0.49 mL, 0.49 mmol, 1.3M in THF). The reaction mixture waswarmed to rt and stirred for 30 minutes, then cooled to −78° C. followedby addition of a solution of compound from step 281a (100 mg, 0.221mmol) in THF (1 mL). The reaction mixture was stirred for 18 h, slowlywarming to rt and quenched by aq. NH₄Cl. It was extracted with EtOAc andwashed with brine and dried (Na₂SO₄). After being concentrated, thecrude was chromatographed (silica, acetone/hexanes) to give the desiredcompound (11 mg, 9%). ESI-MS m/z=575.12, 577.12 [M+HCO₂]⁻.

Step 284b. To a solution of compound of step 284a (11 mg, 0.02 mmol) inNMP (1 ml), was added p-TSA (20 mg, 0.105 mmol) and m-CPBA (20 mg, 0.089mmol, 77%) and stirred at rt o/n. The reaction was extracted with EtOAc,washed with water and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated. The crude product was chromatographed(silica, hexane/acetone) to give the title compound as white solid (6mg, 51%). ESI-MS m/z=607.13, 609.13 [M+HCO₂]⁻.

Example 284a

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 284 via SFC chromatography,earlier eluting compound.

Example 284b

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 284 via SFC chromatography, latereluting compound.

Example 285

Step 285a. To a solution of 3-bromopyridine (46 μL, 0.49 mmol) in THF (1mL) at 0° C. was added isopropylmagnesium chloride, lithium chloridecomplex (0.49 mL, 0.49 mmol, 1.3M in THF). The reaction mixture waswarmed to rt and stirred for 30 minutes, then cooled to −78° C. followedby addition of a solution of compound from step 281a (100 mg, 0.221mmol) in THF (1 mL). The reaction mixture was stirred for 18 h, slowlywarming to rt and quenched by aq. NH₄Cl. It was extracted with EtOAc andwashed with brine and dried (Na₂SO₄). After being concentrated, thecrude was chromatographed (silica, acetone/hexanes) to give the desiredcompound (15 mg, 13%). ESI-MS m/z=575.12, 577.12 [M+HCO₂]⁻.

Step 285b. To a solution of compound of step 285a (15 mg, 0.028 mmol) inNMP (1 ml), was added p-TSA (20 mg, 0.105 mmol) and m-CPBA (20 mg, 0.089mmol, 77%) and stirred at rt o/n. The reaction was extracted with EtOAc,washed with water and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated. The crude product was chromatographed(silica, hexane/acetone) to give the title compound as white solid (8mg, 50%). ESI-MS m/z=607.13, 609.13 [M+HCO₂]⁻.

Example 285a

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 285 via SFC chromatography,earlier eluting compound.

Example 285b

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 285 via SFC chromatography, latereluting compound.

Example 286

Step 286a. To a solution of 4-iodopyridine (159 mg, 0.774 mmol) in THF(1.5 mL) at 0° C. was added n-butyllithium (0.31 mL, 0.774 mmol, 2.5M inhexanes). This reaction mixture was warmed to rt and stirred for 30minutes, then cooled to −78° C. followed by addition of a solution ofcompound from step 281a (100 mg, 0.221 mmol) in THF (1 mL). The reactionmixture was stirred for 18 h, slowly warming to rt and quenched by aq.NH₄Cl. It was extracted with EtOAc and washed with brine and dried(Na₂SO₄). After being concentrated, the crude was chromatographed(silica, acetone/hexanes) to give the desired compound (45 mg, 38%).ESI-MS m/z=575.30, 577.30[M+HCO₂]⁻.

Step 286b. To a solution of compound of step 286a (45 mg, 0.085 mmol) inNMP (2 ml), was added p-TSA (48 mg, 0.254 mmol) and m-CPBA (57 mg, 0.254mmol, 77%) and stirred at rt o/n. The reaction was extracted with EtOAc,washed with water and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated. The crude product was chromatographed(silica, hexane/acetone) to give the title compound as white solid (8mg, 17%). ESI-MS m/z=607.29, 609.29 [M+HCO₂]⁻.

Example 287

Step 287a. To a solution of 1-(diethoxy)-1H-imidazole (159 mg, 0.487mmol) in THF (1 mL) at −78° C. was added n-butyllithium (0.195 mL, 0.487mmol, 2.5M in hexanes). The reaction mixture stirred for 30 minutesfollowed by addition of a solution of compound from step 281a (100 mg,0.221 mmol) in THF (1 mL). The reaction mixture was stirred for 18 h,slowly warming to rt and quenched by aq. NH₄Cl. It was extracted withEtOAc and washed with brine and dried (Na₂SO₄). After beingconcentrated, the crude was chromatographed (silica, acetone/hexanes) togive the desired compound (22 mg, 38%). ESI-MS m/z=564.29,566.29[M+HCO₂]⁻.

Step 287b. To a solution of compound of step 287a (22 mg, 0.042 mmol) inNMP (2 ml), was added p-TSA (50 mg, 0.263 mmol) and m-CPBA (50 mg, 0.223mmol, 77%) and stirred at rt o/n. The reaction was extracted with EtOAc,washed with water and brine. The organic layer was dried (Na₂SO₄),filtered and concentrated. The crude product was chromatographed viaprep-HPLC (C18, acetonitrile/water) to give the title compound as whitesolid (6 mg, 26%). ESI-MS m/z=596.28, 598.28 [M+HCO₂]⁻.

Example 288

Step 288a. To a solution of 1-methyl-1H-pyrazole (64 μL, 0.774 mmol) inTHF (1.5 mL) at 0° C. was added n-butyllithium (0.31 mL, 0.774 mmol,2.5M in hexanes). The reaction mixture stirred for 30 minutes followedby addition of a solution of compound from step 281a (100 mg, 0.221mmol) in THF (1 mL). The reaction mixture was stirred for 18 h, slowlywarming to rt and quenched by aq. NH₄Cl. It was extracted with EtOAc andwashed with brine and dried (Na₂SO₄). After being concentrated, thecrude was chromatographed (silica, acetone/hexanes) to give the desiredcompound (79 mg, 67%). ESI-MS m/z=578.32, 580.31 [M+HCO₂]⁻.

Step 288b. To a solution of compound of step 288a (79 mg, 0.148 mmol) inNMP (2 ml), was added m-CPBA (99 mg, 0.444 mmol, 77%) and stirred at rto/n. The reaction was extracted with EtOAc, washed with water and brine.The organic layer was dried (Na₂SO₄), filtered and concentrated. Thecrude product was chromatographed (silica, acetone/hexanes) to give thetitle compound as white solid (65 mg, 78%). ESI-MS m/z=610.30, 612.30[M+HCO₂]⁻.

Example 289

Step 289a. To a solution of 4-bromo-1-methyl-1H-pyrazole (69 μL, 0.664mmol) in THF (2 mL) at −78° C. was added n-butyllithium (0.266 mL, 0.664mmol, 2.5M in hexanes). The reaction mixture stirred for 30 minutesfollowed by addition of a solution of compound from step 281a (100 mg,0.221 mmol) in THF (1 mL). The reaction mixture was stirred for 18 h,slowly warming to rt and quenched by aq. NH₄Cl. It was extracted withEtOAc and washed with brine and dried (Na₂SO₄). After beingconcentrated, the crude was chromatographed (silica, acetone/hexanes) togive the desired compound (23 mg, 19%). ESI-MS m/z=578.31, 580.31[M+HCO₂]⁻.

Step 289b. To a solution of compound of step 289a (23 mg, 0.148 mmol) inNMP (2 ml), was added m-CPBA (29 mg, 0.444 mmol, 77%) and stirred at rto/n. The reaction was extracted with EtOAc, washed with water and brine.The organic layer was dried (Na₂SO₄), filtered and concentrated. Thecrude product was chromatographed (silica, acetone/hexanes) to give thetitle compound as white solid (22 mg, 90%). ESI-MS m/z=610.30, 612.31[M+HCO₂]⁻.

Example 290

Step 290a. To a solution of oxazole (76 μL, 1.162 mmol) in THF (1.5 mL)at 0° C. was added i-PrMgCl—LiCl (0.894 mL, 1.162 mmol, 1.3M in THF).The reaction mixture stirred for 30 minutes followed by addition of asolution of compound from step 281a (150 mg, 0.332 mmol) in THF (1.5mL). The reaction mixture was stirred for 3 h, slowly warming to rt andquenched by aq. NH₄Cl. It was extracted with EtOAc and washed with brineand dried (Na₂SO₄). After being concentrated, the crude waschromatographed (silica, acetone/hexanes) to give the desired compound(22 mg, 38%). ESI-MS m/z=565.28, 567.28 [M+HCO₂]⁻.

Step 290b. To a solution of compound of step 290a (133 mg, 0.042 mmol)in NMP (2.5 ml), was added p-TSA (243 mg, 1.276 mmol) and m-CPBA (172mg, 0.766 mmol, 77%) and stirred at rt o/n. The reaction was extractedwith EtOAc, washed with water and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated. The crude product waschromatographed via prep-HPLC (C18, acetonitrile/water) to give thetitle compound as white solid (20 mg, 14%). ESI-MS m/z=597.26, 599.26[M+HCO₂]⁻.

Example 291

Step 291a. To a solution of 2-bromo-5-fluoropyridine (302 mg, 1.715mmol) in THF (3 mL) was added n-butyllithium (0.730 ml, 1.826 mmol, 2.5Min THF) dropwise at −78° C. After being stirred for 1 h at the sametemperature, a solution of the compound from step 281a (250 mg, 0.553mmol) in THF (1.5 mL) was added into the mixture at −78° C. The reactionwas slowly warmed to rt and stirred for 16 h. Sat. NH₄Cl solution wasadded. The mixture was extracted with EtOAc, dried over Na₂SO₄, andpurified by column chromatography (silica. MeOH/DCM) to give the desiredcompound (70 mg, 0.128 mmol, 23% yield) as pale brown solid.

Step 291b. To a solution of the compound from step 291a (70 mg, 0.128mmol), p-TSA (72.8 mg, 0.383 mmol) in NMP (1 mL) was added m-CPBA (86mg, 0.383 mmol, 77%) at 0° C. The reaction was slowly warmed to rt andstirred for 16 h. Sat. Na₂S₂O₃ solution and NaHCO₃ solution were addedand the resulting mixture was stirred for 1 h at rt. The mixture wasextracted with EtOAc, washed with sat. Na₂S₂O₃ solution and NaHCO₃solution (×2), brine, and dried over Na₂SO₄. The crude material waspurified by column chromatography (silica, MeOH/DCM) to give the titlecompound (17.0 mg, 0.128 mmol, 23% yield) as light brown solid. ESI-MSm/z=580.00, 582.01 [M−H]⁻.

Example 291a

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 291 via SFC chromatography,earlier eluting compound.

Example 291b

The title compound (single enantiomer, tentatively assigned) wasisolated from the compound of example 291 via SFC chromatography, latereluting compound.

Example 292

The crude material from step 291b was purified by column chromatography(0-20% MeOH in DCM) to give the title compound (9.3 mg, 0.016 mmol, 12%yield) as light brown solid. ESI-MS m/z=596.00, 598.01 [M−H]⁻.

Example 293

Step 293a. To a solution of 2-bromo-5-methylpyridine (200 mg, 1.16 mmol)in THF (1.5 mL) at −78° C. was added n-butyllithium (0.465 mL, 1.16mmol, 2.5M in hexane). The reaction mixture stirred for 30 minutesfollowed by addition of a solution of compound from step 281a (150 mg,0.332 mmol) in THF (1.5 mL). The reaction mixture was stirred for 1 h,slowly warming to rt and quenched by aq. NH₄Cl. It was extracted withEtOAc and washed with brine and dried (Na₂SO₄). After beingconcentrated, the crude was chromatographed (silica, acetone/hexanes) togive the desired compound (129 mg, 71%). ESI-MS m/z=589.14, 591.14[M+HCO₂]⁻.

Step 293b. To a solution of compound of step 293a (129 mg, 0.24 mmol) inNMP (2.4 ml), was added p-TSA (225 mg, 1.18 mmol) and m-CPBA (159 mg,0.71 mmol, 77%) and stirred at rt o/n. The reaction was extracted withEtOAc, washed with water and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated. The crude product waschromatographed (silica, hexane/acetone) to give the title compound aswhite solid (109 mg, 80%). ESI-MS m/z=621.13, 623.13 [M+HCO₂]⁻.

Example 297

Step 297a. To a solution of 2-bromo-3-fluoropyridine (204 mg, 1.16 mmol)in THF (1.5 mL) at −78° C. was added n-butyllithium (0.465 mL, 1.16mmol, 2.5M in hexane). The reaction mixture stirred for 30 minutesfollowed by addition of a solution of compound from step 281a (150 mg,0.332 mmol) in THF (1.5 mL). The reaction mixture was stirred for 1 h,slowly warming to rt and quenched by aq. NH₄Cl. It was extracted withEtOAc and washed with brine and dried (Na₂SO₄). After beingconcentrated, the crude was chromatographed (silica, acetone/hexanes) togive the desired compound (10 mg, 5.5%). ESI-MS m/z=563.12, 565.10[M+HCO₂]⁻. Also isolated was3-(((1R,3r,5S,8r)-8-((2-bromo-3-fluoropyridin-4-yl)(hydroxy)methyl)-8-hydroxybicyclo[3.2.1]octan-3-yl)thio)-4-chloro-N-(3,4-difluorophenyl)benzamide(77 mg, 37%). ESI-MS m/z=671.03, 673.04 [M+HCO₂]⁻

Step 297b. To a solution of compound of step 297a (10 mg, 0.018 mmol) inNMP (0.2 ml), was added p-TSA (17 mg, 0.09 mmol) and m-CPBA (12 mg,0.055 mmol, 77%) and stirred at rt. o/n. The reaction was extracted withEtOAc, washed with water and brine. The organic layer was dried(Na₂SO₄), filtered and concentrated. The crude product waschromatographed (silica, hexane/acetone) to give the title compound aswhite solid (4.7 mg, 44%). ESI-MS m/z=625.11, 627.11 [M+HCO₂]⁻.

Example 298

Step 298. To a solution of side-product from step 297a(3-(((1R,3r,5S,8r)-8-((2-bromo-3-fluoropyridin-4-yl)(hydroxy)methyl)-8-hydroxybicyclo[3.2.1]octan-3-yl)thio)-4-chloro-N-(3,4-difluorophenyl)benzamide(77 mg, 0.123 mmol) in NMP (1.3 ml), was added p-TSA (117 mg, 0.613mmol) and m-CPBA (82 mg, 0.368 mmol, 77%) and stirred at rt o/n. Thereaction was extracted with EtOAc, washed with water and brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated. The crudeproduct was chromatographed (silica, hexane/acetone) to give the titlecompound as white solid (64 mg, 79%). ESI-MS m/z=703.01, 705.12[M+HCO₂]⁻.

Example 307

Step 307a. To the mixture of compound from example 150d (7.04 g, 16.61mmol) in ACN (70 ml) and DBU (3.25 ml, 21.59 mmol) at 0° C.Nonafluorobutane-1-sulfonyl fluoride (5.52 g, 18.27 mmol) was added viaa pipette in one min and stirred at such temperature for 1 h. When itwas still cooled, MTBE 200 mL was added. The solution was washed withwater, with 1 N HCl twice, then water, aq. NaHCO₃ twice, brine twice.After being dried (Na₂SO₄) and concentrated, 13.5 g light yellow solidwas obtained. To it MTBE/Hexanes 1:10 (200 mL) was added and stirred atrt for 30 mins before filtered under vacuum. The solid collected waswashed with MTBE/hexanes (1:10, 100 mL) to give (10.1 g, 86%) off whitesolid. ESI-MS m/z=704.02, 706.02 [M−H]⁻.

Step 307b. To the solution of compound from step 307a (200 mg, 0.283mmol) in DMF (2 mL), methyl isopropylamine (0.15 mL) was added stirredat 75° C. for two days. The crude was diluted with EtOAc, washed withwater twice, brine twice and dried (Na₂SO₄) and concentrated. The crudewas chromatographed (silica, MeOH/DCM) to give desired compound as amixture with other impurities. ESI-MS m/z=477.15, 479.15 [M−H]⁻.

Step 307c. The title compound was obtained from the compound of step307b following the procedure described in example 284b and purified byprep-HPLC. ESI-MS m/z=509.14, 511.14 [M−H]⁻.

Example 308

To the compound form step 82a (570 mg, 1.27 mmol) in THF (10 mL), m-CPBA(77% w/w, 1.42 g, 6.33 mmol) was added and stirred at rt o/n. To it, aq.Na₂S₂O₃ (10 mL) and NaHCO₃ (10 mL) were added, followed by 4 drops TEAand EtOAc (50 mL). It was stirred at rt for 1.5 hour before beingseparated. The aq. phase was extracted with EtOAc. The combined organicwas washed with NaHCO₃, brine and dried (Na₂SO₄). After concentrated,the crude light yellow solid was dissolved in MeOH (50 mL) under heating(heat gun) and cooled to rt slowly before kept at 0° C. fro 30 mins. Theformed crystals were collected under vacuum to afford the title compound(510 mg, 81%) as white solid. ESI-MS m/z=496.20, 498.20 [M−H]⁻.

Example 309

To a solution of compound from example 308 (50 mg, 0.10 mmol) in DMF(0.5 mL), 1,1-Dioxoisothiazolidine (18.3 mg, 0.15 mmol) was addedfollowed by K₂CO₃ (14 mg, 0.1 mmol) and stirred at 50° C. o/n. The crudewas purified on prep-HPLC (C-18, Acetonitrile/water) to give the titlecompound (16 mg, 26%) as a white solid. ESI-MS m/z=617.25, 619.25[M−H]⁻.

Example 314

Step 314a. To a slurry of Me₃SOI (365 mg, 1.66 mmol) in DMF (1 mL) wasadded potassium tert-butoxide (186 mg, 1.66 mmol) at 0° C. The mixturewas warmed to rt and stirred for 45 min. The compound from step 281a(150 mg, 0.33 mmol) in DMF (2 mL) was added dropwise into the reactionmixture. After stirring for 4 h at rt, the reaction mixture was cooledto 0° C., sat. NH₄Cl solution was added, extracted with MTBE, and driedover Na₂SO₄. The crude product was purified by column chromatography(0-50% EtOAc in Hex) to give the desired compound (42.0 mg, 0.090 mmol,27% yield) as white solid.

Step 314b. To a solution of the compound from step 314a (42 mg, 0.090mmol) in DMF (2 mL) was added 1H-pyrazole (12.27 mg, 0.180 mmol),potassium carbonate (18.69 mg, 0.135 mmol). The reaction was stirred at65° C. for 15 h. The mixture was extracted with EtOAc, dried overNa₂SO₄, and purified by column chromatography (0-70% EtOAc in Hex) togive the desired compound (30.0 mg, 0.056 mmol, 62% yield) as off-whitesolid.

Step 314c. To a solution of the compound from step 314b (30 mg, 0.056mmol) and 10-camphorsulfonic acid (CSA) (19.57 mg, 0.084 mmol) in NMP(0.2 mL) was added m-CPBA (37.8 mg, 0.169 mmol, 77%) at 0° C. Thereaction was slowly warmed to rt and stirred for 15 h. Sat. Na₂S₂O₃solution and NaHCO₃ solution were added into the mixture and stirred for1 h. The reaction was extracted with EtOAc, washed with sat. Na₂S₂O₃solution and NaHCO₃ solution (×2), brine, and dried over Na₂SO₄. Thecrude material was purified by column chromatography (silica,hexanes/acetone) to give the title compound (20 mg, 0.035 mmol, 63%yield) as off-white solid. ESI-MS m/z=565.30, 567.29 [M−H]⁻.

Example 315

Step 315a. To a solution of oxazolidin-2-one (42.0 mg, 0.483 mmol) inDMF (1 mL) was added sodium hydride (17.38 mg, 0.435 mmol) at 0° C. Themixture was stirred for 1 h at rt, and cooled to 0° C. The compound fromstep 314a (45 mg, 0.097 mmol) in DMF (1 mL) was added into the reaction.The mixture was heated to 55° C. for 15 h. The reaction was cooled to rtand sat. NH₄Cl solution was added. The mixture was extracted with EtOAc,dried over Na₂SO₄, and purified by column chromatography (silica,hexanes/EtOAc) to give the desired compound (40 mg, 0.072 mmol, 75%yield) as white solid.

Step 315b. To a solution of the compound from step 315a (38 mg, 0.069mmol) in NMP (1 mL) was added m-CPBA (46.2 mg, 0.206 mmol, 77%) at 0° C.The reaction was slowly warmed to rt and stirred for 16 h. The mixturewas extracted with EtOAc, washed with sat. Na₂S₂O₃ solution and NaHCO₃solution (×2), brine, and dried over Na₂SO₄. The crude material waspurified by column chromatography (silica, MeOH/DCM) to give the titlecompound (14.0 mg, 0.024 mmol, 35% yield) as off-white solid. ESI-MSm/z=584.02, 586.02 [M−H]⁻.

Example 316

Step 316a. To a solution of 1-(diethoxymethyl)-1H-imidazole (0.053 ml,0.322 mmol) in THF (2 mL) was added n-butyllithium (0.116 ml, 0.290mmol, 2.5M in THF) at −78° C. The mixture was warmed to 0° C. andstirred for 45 min, and then cooled to −78° C. The compound from step314a (30 mg, 0.064 mmol) in THF (1 mL) was added into the reactionmixture. The reaction was heated to 50° C. and stirred for 16 h. Thereaction was cooled to rt and sat. NH₄Cl solution was added. The mixturewas extracted with EtOAc, dried over Na₂SO₄, and purified by columnchromatography (silica, hexanes/acetone) to give the desired compound(13 mg, 0.024 mmol, 38% yield) as an off-white solid.

Step 316b. To a solution of the compound from step 316a (13 mg, 0.024mmol), CSA (8.48 mg, 0.037 mmol) in NMP (1 mL) was added m-CPBA (16.37mg, 0.073 mmol, 77%) at 0° C. The reaction was slowly warmed to rt andstirred for 15 h. The mixture was extracted with EtOAc, washed with sat.Na₂S₂O₃ solution and NaHCO₃ solution (×2), brine, and dried over Na₂SO₄.The crude material was purified by column chromatography (silica,hexanes/acetone) to give the title compound (5.8 mg, 0.010 mmol, 42%yield) as an off-white solid. ESI-MS m/z=565.02, 566.02 [M−H]⁻.

Example 317

Step 317a. To a solution of 4-methylpyridine (0.134 ml, 1.372 mmol) inTHF (3 mL) was added lithium diisopropylamide (1.372 ml, 1.372 mmol, 1Min THF) dropwise at −78° C. The mixture was stirred for 1 h at the sametemperature. A solution of the compound from step 281a (200 mg, 0.443mmol) in THF (1.5 mL) was added into the mixture at −78° C. The reactionwas slowly warmed to rt and stirred for 16 h. Sat. NH₄Cl solution wasadded. The mixture was extracted with EtOAc, dried over Na₂SO₄, andpurified by column chromatography (silica, MeOH/DCM) to give the desiredcompound (91 mg, 0.167 mmol, 38% yield) as a sticky oil.

Step 317b. To a solution of the compound from step 317a (91 mg, 0.167mmol), p-TSA (95 mg, 0.501 mmol) in NMP (1 mL) was added m-CPBA (112 mg,0.501 mmol, 77%) at 0° C. The reaction was slowly warmed to rt andstirred for 16 h. The mixture was extracted with EtOAc, washed with sat.Na₂S₂O₃ solution and NaHCO₃ solution (×2), brine, and dried over Na₂SO₄.The crude material was purified by column chromatography (silica,hexanes/acetone) to give the title compound (61.0 mg, 0.106 mmol, 63%yield) as white solid. ESI-MS m/z=576.04, 578.04 [M−H]⁻.

Example 318

Step 318a. To a solution of 3-methylpyridine (0.134 ml, 1.372 mmol) inTHF (3 mL) was added lithium diisopropylamide (1.372 ml, 1.372 mmol, 1Min THF) dropwise at −78° C. After being stirred for 30 min at the sametemperature, the mixture was warmed to 0° C. and stirred for 30 min andcooled down to −78° C. A solution of the compound from step 281a (200mg, 0.443 mmol) in THF (1.5 mL) was added into the mixture at −78° C.The reaction was slowly warmed to rt and stirred for 15 h. Sat. NH₄Clsolution was added. The mixture was extracted with EtOAc, dried overNa₂SO₄, and purified by column chromatography (silica, MeOH/DCM) to givethe desired compound (70 mg, 0.128 mmol, 29% yield) as a pale yellowsolid.

Step 318b. To a solution of the compound from step 318a (70 mg, 0.128mmol), p-TSA (73.3 mg, 0.385 mmol) in NMP (1 mL) was added m-CPBA (86mg, 0.385 mmol, 77%) at 0° C. The reaction was slowly warmed to rt andstirred for 16 h. Sat Na₂S₂O₃ solution and NaHCO₃ solution were addedand the resulting mixture was stirred for 1 h at rt. The mixture wasextracted with EtOAc, washed with sat. Na₂S₂O₃ solution and NaHCO₃solution (×2), brine, and dried over Na₂SO₄. The crude material waspurified by column chromatography (silica, hexanes/acetone) to give thetitle compound (27.0 mg, 0.047 mmol, 36% yield) as a white solid. ESI-MSm/z=576.04, 578.04 [M−H]⁻.

Example 319

Step 319a. To a solution of 2-methylpyridine (0.135 ml, 1.372 mmol) inTHF (3 mL) was added lithium diisopropylamide (0.549 ml, 1.372 mmol, 1Min THF) dropwise at −78° C. After being stirred for 1 h min at the sametemperature, a solution of the compound from step 281a (200 mg, 0.443mmol) in THF (1.5 mL) was added into the mixture at −78° C. The reactionwas slowly warmed to rt and stirred for 16 h. Sat. NH₄Cl solution wasadded. The mixture was extracted with EtOAc, dried over Na₂SO₄, andpurified by column chromatography (silica, MeOH/DCM) to give the desiredcompound (130 mg, 0.239 mmol, 54% yield) as pale yellow solid.

Step 319b. To a solution of the compound from step 319a (130 mg, 0.239mmol), p-TSA (136 mg, 0.716 mmol) in NMP (1 mL) was added m-CPBA (160mg, 0.716 mmol, 77%) at 0° C. The reaction was slowly warmed to rt andstirred for 16 h. Sat. Na₂S₂O₃ solution and NaHCO₃ solution were addedand the resulting mixture was stirred for 1 h at rt. The mixture wasextracted with EtOAc, washed with sat. Na₂S₂O₃ solution and NaHCO₃solution (×2), brine, and dried over Na₂SO₄. The crude material waspurified by column chromatography (silica, hexanes/acetone) to give thetitle compound (80.0 mg, 0.139 mmol, 58% yield) as white solid. ESI-MSm/z=576.04, 578.04 [M−H]⁻.

Example 320

Step 320a. To a solution of compound from example 82a (450 mg, 1.00mmol) in DCM (5 mL), allylbromide (363 mg, 3.0 mmol) was added followedby Hoveyda-Grubbs 2^(nd) generation catalyst (12.5 mg, 0.2 mmol) andstirred at rt o/n. The reaction was concentrated. The crude waschromatographed (silica, EtOAc/hexanes) to give desired compound (410mg, a mixture of desired and starting material in a ratio 1.1:1) as anoff-white solid. ESI-MS m/z=542.16, 544.16[M−H]⁻.

Step 320b. To a solution of compound from step 320a (170 mg, 0.31 mmol)in DMF (2 mL), Dioxoisothiazolidine (38 mg, 0.31 mmol) was addedfollowed by K₂CO₃ (44 mg, 0.31 mmol) and stirred at 65° C. o/n. Thecrude was diluted with EtOAc, washed with water twice, brine twice anddried (Na₂SO₄) and concentrated. The crude was chromatographed (silica,MTBE/hexanes) to give desired compound (59 mg, 32%) off-white solid.ESI-MS m/z=627.12, 629.12 [M−H+HCOOH]⁻.

Step 320c. The title compound was obtained from the compound of step320b following the procedure described in example 4b. ESI-MS m/z=693.30,695.30 [M−H+HCOOH]⁻.

Example 321

Step 321a. To a solution of compound from step 82a (100 mg, 0.222 mmol)and 3-bromopyridine (26 μL, 0.267 mmol) in DMF (2 mL) was added Et₃N (62μL, 0.445 mmol), tri-o-tolylphosphine (6.8 mg, 0.022 mmol), andpalladium acetate (2.5 mg, 0.011 mmol). The reaction mixture was stirredat 120° C. for 18 h. The reaction mixture was cooled, then extractedwith EtOAc, washed with water and brine, dried over Na₂SO₄ filtered andconcentrated. The crude material was purified by column chromatography(silica, hexane/acetone) to give the desired compound (100 mg, 0.190mmol, 85% yield). ESI-MS m/z=571.30, 573.30 [M−H]⁻.

Step 321b. To a solution compound from step 321a (52 mg, 0.099 mmol) inacetone (1 mL) and water (0.2 mL) was added OsO₄ (25 μL, 4.93 μmol, 5%in water) and NMO (58 mg, 0.493 mmol). The reaction mixture was stirredat rt for 72 h. The reaction mixture was diluted with ethyl acetate andthen washed with saturated Na₂S₂O₃ and saturated NaCl. The organic layerwas dried with Na₂SO₄, filtered and concentrated. The crude material wasused without further purification.

Step 321c. To a solution of crude material from step 321b in NMP (2 mL)was added p-TSA (56 mg, 0.294 mmol) and m-CPBA (110 mg, 0.49 mmol, 77%)and stirred at rt. o/n. The reaction was extracted with EtOAc, washedwith water and brine. The organic layer was dried (Na₂SO₄), filtered andconcentrated. The crude product was chromatographed (silica,hexane/acetone) to give the title compound as white solid. ESI-MSm/z=637.32, 639.32 [M+HCO₂]⁻.

Example 322

Step 322a. To a solution of compound from step 82a (100 mg, 0.222 mmol)and 4-bromo-1-methyl-1H-pyrazole (28 μL, 0.267 mmol) in DMF (2 mL) wasadded Et₃N (62 μL, 0.445 mmol), tri-o-tolylphosphine (6.8 mg, 0.022mmol), and palladium acetate (2.5 mg, 0.011 mmol). The reaction mixturewas stirred at 120° C. for 18 h. The reaction mixture was cooled thenextracted with EtOAc, washed with water and brine, dried over Na₂SO₄filtered and concentrated. The crude material was purified by columnchromatography (silica, hexane/acetone) to give the desired compound (12mg, 0.023 mmol, 10% yield). ESI-MS m/z=574.32, 576.32 [M−H]⁻.

Step 322b. To a solution compound from step 322a (12 mg, 0.099 mmol) inacetone (0.5 mL) and water (0.1 mL) was added OsO₄ (6 μL, 1.13 μmol, 5%in water) and NMO (13 mg, 0.113 mmol). The reaction mixture was stirredat rt for 72 h. The reaction mixture was diluted with ethyl acetate andthen washed with saturated Na₂S₂O₃ and saturated NaCl. The organic layerwas dried with Na₂SO₄, filtered and concentrated. The crude mixture wasused without further purification.

Step 322c. To a solution of crude material from step 322b in NMP (1 mL)was added m-CPBA (16 mg, 0.069 mmol, 77%) and stirred at rt. o/n. Thereaction was extracted with EtOAc, washed with water and brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated. The crudeproduct was chromatographed (silica, hexane/acetone) to give the titlecompound as a white solid. ESI-MS m/z=640.33, 642.33 [M+HCO₂]⁻.

Example 323

Step 323a. To a solution of trimethylsilylacetylene (0.50 ml, 3.56 mmol)in THF (1.66 ml) was added n-BuLi (1.426 ml, 3.56 mmol, 2.5M in THF) at−78° C. The resulting mixture was stirred for 1 h at the sametemperature. A solution of compound from step 281a (0.3 g, 0.664 mmol)in THF (1.66 mL) was added into the reaction at −78° C. The resultinglight yellow solution was slowly warmed up to rt and stirred for 3 h.Sat. NH₄Cl solution was added. The mixture was extracted with EtOAc,dried over Na₂SO₄, and used without further purification.

Step 323b. To a solution of the compound from step 323a (365 mg, 0.664mmol) in MeOH (3 ml) and water (0.3 ml) was added potassium carbonate(459 mg, 3.32 mmol) at rt. The mixture was stirred for 15 h at rt.Solvent removed in vacuo, and the resulting mixture was extracted withEtOAc, dried over Na₂SO₄, and then purified by column chromatography(silica, hexanes/EtOAc) to give the desired compound (204.9 mg, 0.429mmol, 65% yield) as a white solid.

Step 323c. A mixture of formaldehyde (109 μl, 1.465 mmol), acetic acid(12.58 μl, 0.220 mmol) and THF (1 mL) was stirred for 15 min at rt.Sodium azide (14.28 mg, 0.220 mmol) was added, followed by the compoundfrom step 323b (70 mg, 0.146 mmol). The mixture was stirred for 10 min,and sodium ascorbate (5.80 mg, 0.029 mmol) was added, followed bycopper(II) sulfate (1.169 mg, 7.32 μmol) in 150 uL of water. Thereaction was heated to 50° C. and stirred for 16 h, and then extractedwith EtOAc, dried over Na₂SO₄, and then purified by columnchromatography (silica, MeOH/DCM) to give the desired compound (53.4 mg,0.103 mmol, 70% yield) as greenish solid.

Step 323d. To a solution of the compound from step 323c (53.4 mg, 0.102mmol) and p-TsOH (97 mg, 0.512 mmol) in NMP (1 mL) was added m-CPBA(68.9 mg, 0.307 mmol, 77%) at 0° C. The reaction was slowly warmed to rtand stirred for 15 h. Sat. Na₂S₂O₃ solution and NaHCO₃ solution wereadded and the resulting mixture was stirred for 1 h at rt. The mixturewas extracted with EtOAc, washed with sat. Na₂S₂O₃ solution and NaHCO₃solution (×2), brine, and dried over Na₂SO₄. The crude material waspurified by column chromatography (silica, MeOH/DCM with 0.1% NH₃) togive the title compound (15.0 mg, 0.027 mmol, 27% yield) as an off-whitesolid. ESI-MS m/z=549.95, 551.97 [M−H]⁻.

Example 327

Step 327a. Treatment of the compound from step 279d with the conditiondescribed in step Int 2e gave the desired product. ¹H NMR (400 MHz,Chloroform-d) δ 3.90 (m, 1H), 3.43 (s, 2H), 2.69 (s, 1H), 1.84 (m, 4H),1.70 (m 2H), 1.57 (m, 2H), 1.45 (t, J=6.7 Hz, 3H), 0.83 (s, 9H), 0.00(s, 6H).

Step 327b. To a solution of compound of step 327a (10.6 g, 37.0 mmol) inCH₂Cl₂ (74.0 ml) at 0° C. was added pyridine (8.98 ml, 111 mmol), DMAP(0.226 g, 1.850 mmol) and benzenesulfonyl chloride (5.19 ml, 40.7 mmol).After being stirred at rt o/n, water (15 mL) was added and stirred 30mins. It was concentrated then diluted with EtOAc (400 mL) and washedwith saturated aq. NaHCO₃, water, 1M HCl, water, brine. The organiclayer was dried (Na₂SO₄) and concentrated to give the crude product thatwas used for the next step without further purification.

Step 327c. To a solution of step 327b (15.60 g, 36.6 mmol) in2-methyl-THF (58.5 ml) at rt was added conc. HCl (11.70 ml, 140 mmol).The resulting clear solution was stirred at rt for 3 h. The mixture waspoured portion-wise into a mixture of saturated aq. NaHCO₃ and DCM. Theaqueous layer was extracted with DCM twice. The combined organic phasewas washed with brine, dried (Na₂SO₄), filtered and concentrated. Theresidue was dried under vacuum to afford a white solid which was useddirectly for next step.

Step 327d. To a solution of compound of step 327c (11.42 g, 36.6 mmol)in CH₂Cl₂ (122 ml) at 0° C. was added DMAP (0.447 g, 3.66 mmol),pyridine (8.87 ml, 110 mmol) and acetic anhydride (3.79 ml, 40.2 mmol).The reaction was stirred at rt overnight. Saturated aq. NaHCO₃ (30 mL)was added and stirred 15 mins. After separated, the aq. phase wasextracted with CH₂Cl₂ (100 mL×2), the combined organic phases were dried(Na₂SO₄) and concentrated. The crude was chromatographed to give thedesired compound (11.4 g, 93% three steps) as off-white solid.

Step 327e. To a solution of compound from step 327d (4.000 g, 11.29mmol) in acetic acid (45 ml) at rt was added manganesebis(trifluoromethanesulfonate) (0.91 ml, 0.011 mmol) (0.0125 M in aceticacid/water 9/1) and 2,2′-bipyridine (0.018 g, 0.113 mmol). After beingstirred 10 min at rt, peracetic acid/KOH mixture (prepared by adding 10%KOH (3.0 ml) to 35% peracetic acid (10.0 ml), 11.79 ml, 39.5 mmol) wasadded dropwise over ˜10 min. It was further stirred 15 mins at rtfollowed by addition of acetone (130 ml). After 1 min at rt, theslightly cloudy solution was filtered through a short pad of celite,washed with acetone. The filtrate was concentrated. The crude residuewas chromatographed (silica, EtOAc/hexanes) to afford desired compound(2.130 g, 51%) as colorless oil.

Step 327f. To a clear solution of step 327e (2.130 g, 5.78 mmol) andintermediate 6 (1.820 g, 6.07 mmol) in DMF (5.78 ml) at rt was addedpotassium carbonate (0.799 g, 5.78 mmol). The mixture was stirred at 70°C. for 12 h before being cooled. The mixture was diluted with EtOAc andsaturated NH₄Cl solution. The organic layer was washed with water/brine(1/1, *2), brine (*1), dried and concentrated. The crude residue waschromatographed (silica, EtOAc/DCM) to afford desired compound (2.10 g,70%). ESI-MS m/z=508.07, 510.07 [M−H]⁻.

Step 327g. To a solution of compound from step 327f (40 mg, 0.078 mmol)in EtOH at 0° C. was added NaBH₄ (6 mg, 0.16 mmol). 30 mins later 2ndportion 2 eq. NaBH₄ was added and stirred at rt for 3 hours. total ˜10eq. NaBH₄ was added. It was concentrated to remove the volatile. Thecrude was dissolved in EtOAc and washed with NH₄Cl and brine, driedconcentrated to give the crude desire compound (60 mg) as white solid.This material was used in the next step without further purification.ESI-MS m/z=468.08, 470.08 [M−H]⁻.

Step 327h. The title compound was obtained from step 327g, by followedthe procedure described in example 130b. ESI-MS m/z=500.07, 502.07[M−H]⁻.

Example 328

Step 328a. To the compound from step 327f (610 mg, 1.2 mmol) in EtOH (50mL)/MeOH (15 mL) at 0° C., NaBH₄ (360 mg, 9.6 mmol) was added. 15 minslater 2^(nd) portion NaBH₄ (200 mg) was added. 10 mins later, 3^(rd)portion NaBH₄ (100 mg) was added, stirred another 10 mins. When stillcooled, diluted HCl (0.5 M) was added dropwise until no more bubbling.EtOAc (200 mL) was added, followed by water 50 mL. The organic waswashed with water, brine, dried (Na₂SO₄) and concentrated. The cruderesidue was chromatographed (silica, EtOAc/hexanes) to afford desiredcompound (410 mg, 67%) as a white solid. ESI-MS m/z=510.09,512.09[M−H]⁻.

Step 328b. To solution of the compound of step 328a (382 mg, 0.77 mmol)in toluene (1 mL), 2-(tributyl-15-phosphaneylidene)acetonitrile (647 mg,2.68 mmol) in toluene (3 mL) was added. it was heated at 95 to 100° C.for 1 h, 2^(nd) portion 2-(tributyl-15-phosphaneylidene)acetonitrile(400 mg) was added and heated another 1.5 h. 3^(rd) portion2-(tributyl-15-phosphaneylidene)acetonitrile (500 mg) the was added, andheated another 1.5 h before being cooled and concentrated, the crudeproduct was chromatographed (silica, MTBE/hexanes) to give desiredcompound (302 mg 80%) as white solid. ESI-MS m/z=492.08, 494.08[M−H]⁻.

Step 328c. To the compound form step 328b (295 mg, 0.60 mmol) in aceticanhydride (5 mL), BF₃ etherate (0.6 mL, 4.8 mmol) was added and stirredat rt for 30 mins. The reaction was added into an aq. NaHCO₃ (40 mL) inan ice water bath slowly. It was extracted with EtOAc twice. Thecombined organic was washed with water, brine and dried (Na₂SO₄). Afterbeing concentrated, the crude residue was chromatographed (silica,EtOAc/hexanes) to afford desired compound (245 mg, 69%) as a whitesolid, a mixture of bis-acetates and tri-acetates. ESI-MS m/z=552.10,554.10[M−H]⁻ (bis-acetates), m/z=594.11, 596.11[M−H]⁻ (tri-acetates).

Step 328d. K₂CO₃ (183 mg, 1.33 mmol) was added into the solution of thecompound from step 328c (245 mg, 0.44 mmol) in MeOH (3 mL). 2 hourslater extra K₂CO₃ (25 mg) was added and stirred for another 1 h beforebeing diluted with EtOAc and washed with water. The aqueous phase wasextracted with EtOAc. The combined organic phase was washed with brine,dried (Na₂SO₄) and concentrated. The crude was chromatographed (silica,MTBE/hexanes) to give desired compound (148 mg, 71%) off-white solid.ESI-MS m/z=468.08, 470.08[M−H]⁻.

Step 328e. The title compound was obtained from compound of step 328dfollowing the procedure described in example 130b. ESI-MS m/z=500.07,502.07 [M−H]⁻.

Example 329

To a solution of compound from example 150 (250 mg, 0.514 mmol) inacetonitrile (5 mL) was added(2R,3R,4S,5S,6S)-2-bromo-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (613 mg, 1.543 mmol) and Ag₂CO₃ (1.42 g, 2.57 mmol, 50% w/won celite). The reaction mixture was heated at 80° C. for 18 h. Thecrude reaction mixture was filtered through celite, concentrated andpurified via chromatography (silica, acetone/hexanes) to give titlecompound (195 mg, 47%). ESI-MS m/z=846.17, 848.16 (M+HCO₂)⁻.

Example 330

To a solution of compound from example 329 (195 mg, 0.243 mmol) in THF(3 mL), methanol (1 mL), and water (2 mL) was added LiOH (50 mg, 2.09mmol). The reaction mixture was heated at 40° C. for 1 h. The crudereaction mixture was diluted with EtOAc and acidified to pH 4 with 1MHCl. The organic layer was washed with brine, dried over Na₂SO₄ filteredand concentrated. The crude product was purified via prep-HPLC (C18,acetonitrile/water) to give title compound (10 mg, 6%). ESI-MSm/z=660.11, 662.11 (M−H)⁻.

Example 331

A mixture of example 182 (159 mg, 0.30 mmol) and MX (101 mg, 0.36 mmol)in DMSO (1.5 mL) was stirred at rt for 4 h. Aq. Na₂S₂O₃ solution wasadded and the mixture was extracted with EtOAc. The organic layer waswashed with water, brine, dried over Na₂SO₄, filtered, concentrated andpurified by prep-HPLC (C18 column, acetonitrile/water) to give titlecompound (58 mg, 36%). ESI-MS m/z=572.27, 574.27 (M+HCO₂)⁻.

Example 332

To a solution of the compound from step 331 (230 mg, 0.436 mmol) in THF(5 ml) was added methylmagnesium bromide (0.508 ml, 1.525 mmol) at −78°C. It was stirred for 3 h at the same temperature. Water was added, andthe mixture was extracted with EtOAc, dried over Na₂SO₄. The crudematerial was purified by column chromatography (silica, hexanes/acetone)to the title compound (34.3 mg, 0.063 mmol, 15% yield) as white solid.ESI-MS m/z=541.01, 543.01 [M−H]⁻.

Example 333

Step 333a. A mixture of compound from step 82a (112 mg, 0.25 mmol),E-hex-3-ene (630 mg, 7.5 mmol) and Hoveyda-Grubbs catalyst 2^(nd)Generation (15.7 mg, 0.025 mmol) in DCM (2.0 mL) was stirred at rt for20 h. The mixture was purified by column chromatography (silica,hexanes/EtOAc) to give the desired compound as white solid (78 mg, 65%).ESI-MS m/z=476.13, 478.13 [M−H]⁻.

Step 333b. To a suspension of compound from step 333a (78 mg, 0.163mmol) and NMO (0.115 g, 0.98 mmol) in acetone-water (2.1 mL/0.3 mL) atrt was added osmium tetroxide (0.205 ml 2.5% in t-butanol, 0.016 mmol)and the mixture was stirred at rt for 20 h. It was quenched with aqueousNa₂SO₃, extracted with EtOAc, washed with water, 3N HCl, NaHCO₃, brine,dried over Na₂SO₄, filtered and concenrated to give a mixture of sulfoneand sulfoxide, used without further purification.

Step 333c. To a solution of compound from step 333b in NMP (2 mL) wasadded m-CPBA (0.183 g, 0.85 mmol, 77%) and stirred at rt for 20 h.Aqueous Na₂S₂O₃, NaHCO₃ and few drops of Et₃N was added and stirred atrt for 1 h. It was extracted with EtOAc, washed with water, brine, driedover Na₂SO₄, filtered, concentrated and purified by prep-HPLC (C18,acetonitrile/water) to give racemic product. The racemic product wasseparated by chiral SFC using MeOH as eluent to give the title compound(18 mg, 20%). ESI-MS m/z=542.29, 544.29 [M−H]⁻.

Example 334

Step 334. The title compound (18 mg, 20%) was isolated from example 333.ESI-MS m/z=542.29, 544.29 [M−H]⁻.

Example 336

A solution of the compound of Example 182 (1.05 g, 1.98 mmol) and IBX(0.777 g, 2.77 mmol) in DMSO (5 mL) was stirred at rt for overnight. Itwas quenched with Na₂S₂O₃ aqueous solution and NaHCO₃ aqueous solution.The reaction mixture was extracted with EtOAc, washed with water andbrine, dried over Na₂SO₄, filtered, and concentrated. The resultingcrude product was purified by prep-HPLC (C18, acetonitrile/water) togive the title compound (32 mg, 3.1%) as a white solid. ESI-MSm/z=570.26, 572.26 [M+HCO₂]⁻.

Example 337

Step 337a. To a solution of compound from step int 2a (92.0 g, 676 mmol)in THF (135 ml) at 0° C. was added a solution of prop-1-yn-1-ylmagnesiumbromide (1554 ml, 777 mmol) via cannula 30 minutes. It was stirred 5mins before the ice bath was removed. The mixture was warmed up to rtand kept at rt for 30 mins. The reaction mixture cooled to 0° C.,saturated aq. NH₄Cl (500 mL) was added, followed by MTBE (500 mL). Theaqueous phase was separated and extracted with MTBE (500 mL). Thecombined organic phases were washed with brine and dried (Na₂SO₄). Thesolution past through a short column of silica gel and concentrated togive a yellow oil (125 g, 105% yield).

Step 337b. To a solution of compound from step 337a (50.0 g, 284 mmol)in dioxane (400 mL) and water (133 mL) at 0° C. was added 2,6-lutidine(66.1 ml, 567 mmol) and sodium periodate (212 g, 993 mmol), followed bythe addition of a solution of OsO₄ (1.803 ml, 0.284 mmol, 4% in water).This mixture was warmed up to rt and stirred at rt for 2 days, thencooled to 0° C. and quenched with saturated Na₂S₂O₃ aq solution. Themixture was stirred at 0° C. for 1 h, then diluted with 1 L water,extracted with MTBE (1 L×3). The combined organic phases were washedwith 1N HCl twice, water, NaHCO₃ aq solution, water and brine, dried(Na₂SO₄), and concentrated. The crude residue was chromatographed toafford the desired product (40.2 g, 80%) off-white solid.

Step 337c. A solution of LAH (1M in THF, 265 mL, 265 mmol) and DME (430mL) was cooled at 0° C. A solution of compound form step 337b (18.9 g,106 mmol) in DME (80 mL) was added dropwise in about 0.5 h and stirredone more hour. It was heated to and kept at 80° C. for 2 h before beingcooled to 0° C. It was quenched carefully with 10 mL water and 10 mL 15%NaOH solution, 30 mL water, followed by the addition of 72 g of Na₂SO₄solid and stirred for 1 h before being filtered. After concentration,the crude residue was chromatographed to afford the desired product(12.6 g, 65%) off-white solid.

Step 337d. Into a solution of step 337c (4.58 g, 25.1 mmol) indichloromethane (50 mL) at rt was added pyridine (4.1 mL, 50 mmol) andbenzenesulfonyl chloride (5.33 g, 30.2 mmol). The reaction was stirredo/n at rt before water (30 mL) was added. The mixture was stirred for 1h. After separation, the aqueous phase was extracted with DCM (100 mL).The combined organic phase was washed with HCl (1 M, 20 mL*2), water,NaHCO₃, brine and dried (Na₂SO₄). After being concentrated, the cruderesidue was chromatographed to afford the desired product (6.67 g, 82%)off-white solid.

Step 337e. To a solution of K₂OsO₆.2H₂O (381 mg, 1.03 mmol), (DHQ)₂PHAL(1.61 mg, 2.07 mmol), K₂CO₃ (8.58 g, 62.1 mmol), and K₃FeCN₆ (20.4 g,62.1 mmol) in t-BuOH (40 mL)/water (40 mL) at 0° C. was added compoundfrom step 337d (6.67 g, 20.69 mmol) and MeSO₂NH₂ (5.90 g, 62.1 mmol).The reaction was warmed to rt and stirred one day. It was cooled to 0°C. and Na₂SO₃ (30 g) was added. The mixture was stirred 15 mins at 0°C., then 1 hour at rt before partition with EtOAc (50 mL). The aq. phasewas back extracted with EtOAc. The combined organic was washed with aq.Na₂S₂O₃, water, 1 N HCl (20 mL*2), water, 2 M KOH (10 mL*2), water,brine*2. It was dried (Na₂SO₄) and concentrated to give the desiredproduct (7.20 g, 97%) as an off-white solid. This material was used inthe next step without further purification.

Step 337f. To a solution of compound of step 337e (7.20 g, 20.20 mmol)in CH₂Cl₂ (50 ml) at 0° C. was added DIPEA (14.11 ml, 81 mmol) andacetic anhydride (5.72 ml, 60.6 mmol). The reaction was stirred at rtovernight. Saturated aq. NaHCO₃ (30 mL) was added and stirred 15 mins.After separation, the aq. phase was extracted with CH₂Cl₂ (100 mL×2),the combined organic phases were dried (Na₂SO₄) and concentrated. Thecrude was chromatographed to give the desired compound (8.2 g, 100%) asoff-white solid.

Step 337g. To a clear solution of compound from step 337f (5.09 g, 11.55mmol) in hexfluoroisopropanol (40 ml) at rt was added manganesebis(trifluoromethanesulfonate) (20 mg ml, 0.058 mmol) and2,2′-bipyridine (0.09 g, 0.58 mmol). After being stirred 10 min at rt,peracetic acid/KOH mixture (prepared by adding 10% KOH (3.0 ml) to 35%peracetic acid (10.0 ml), 11.79 ml, 39.5 mmol)) was added via a syringepump over 1 h. Acetone (100 ml) was added. After stirring 10 mins, itwas concentrated. The crude residue was chromatographed (silica,EtOAc/hexanes) to afford recovered starting material 3.1 g and thehigher polar mixture 1.79 g. This high polar mixture was used in thenext step directly.

Step 337h. To a solution of the high polar mixture from step 337g wasadded intermediate 6 by following the step 327f to afford two setmixtures. One set mixture contains the ketone product; ESI-MSm/z=640.31, 642.31 [M+HCOO—]⁻. The other set contains the alcoholproduct. ESI-MS m/z=642.32, 644.32 [M+HCOO—]⁻.

Step 337i. The alcohol product from step 337h was treated with theconditions described in steps 328d and 328e sequentially and purified byprep-HPLC (C-18, Acetonitrile/water) to offer the title compound as awhite solid. ESI-MS m/z=590.27, 592.27 [M+HCOO—]⁻.

Example 339

Step 339a. To a solution of intermediate 2a (2.29 g, 16.8 mmol) in THF(18 mL) at 0° C. was added ethynylmagnesium bromide (40.4 mL, 20.2 mmol,0.5 M in THF) and stirred at 0° C. for 30 mins. The reaction wasquenched by slowly addition of aq. NH₄Cl. MBTE and water were added. Themixture was separated and the organic layer was washed with water andbrine. The mixture was dried over Na₂SO₄, filtered and concentratedunder vacuum to give desired product (2.73 g, 100%).

Step 339b. To a solution of compound from step 339a (1.7 g, 8.38 mmol)in THF (12 mL) at 0° C. was added n-BuLi (7.38 mL, 18.4 mmol, 2.5 M inhexanes) dropwise. After 20 mins at 0° C. CD₃I (0.69 mL, 10.9 mmol) wasadded and the mixture was stirred at rt for 20 h. The reaction wasquenched by slowly addition of aq. NH₄Cl. MBTE and water were added. Themixture was separated, and the organic layer was washed with water andbrine. The mixture was dried over Na₂SO₄, filtered, concentrated undervacuum. The crude product was chromatographed (silica, hexanes/MBTE) togive the desired product (1.09 g, 65%).

Step 339c. To a solution of compound from step 339b. (0.986 g, 5.5 mmol)in dioxane-water (12/4 mL), 2,6-lutidine (1.45 mL, 11 mmol.), and OsO₄(0.18 mL 2.5% solution in t-butanol, 0.017 mmol) were added. The mixturewas cooled and NaIO₄ (4.12 g, 19.25 mmol) was added. The suspension wasstirred at rt for 16 hours. Aq. Na₂S₂O₃ solution was added. The mixturewas stirred for 1 hour and filtered through celite. The mixture wasextracted with MBTE/Hexanes. The organic phase was washed with water, 1N HCl, Sat. NaHCO₃ and brine, dried over Na₂SO₄, filtered andconcentrated to give the crude product (0.64 g, 64.2%).

Step 339d. To a solution of compound from step 339c (0.64 g, 3.53 mmol)in CD₃OD (10 mL) was added MeONa (23 mg, 0.42 mmol) and the mixture wasstirred at rt for 3 h. It was concentrated, and the residue wasredissolved in CD₃OD (5 mL) and stirred for 3 h. The same reaction cyclewas repeated two more times and the solution was quenched with D₂O. Themixture was extracted with MBTE. The organic layer was washed with D₂Oand sat. NaCl solution in D₂O, dried over Na₂SO₄, filtered andconcentrated under vacuum to give the desired compound (0.62 g, 95%).

Step 339e. To a solution of LiBH₄ (3.35 mL, 6.70 mmol, 2M solution inTHF) at −40° C. was added compound from step 339d (0.62 g, 3.35 mmol) inMBTE (20 mL). The resulting solution was warmed up to 0° C. in 1 h. Thereaction was quenched by slowly addition of aq. NH₄Cl. MBTE and waterwere added. The mixture was separated, and the organic layer was washedwith brine. The mixture was dried over Na₂SO₄, filtered and concentratedunder vacuum. The crude product was chromatographed (silica,hexanes/MBTE) to give the desired compound as white solid (0.45 g, 72%).

Step 339f. A solution of compound from step 339e (0.45 g, 2.40 mmol),LAH (6.01 mL, 6.01 mmol, 1M in THF) and MeONa (26 mg, 0.48 mmol) in DME(12 mL) was heated to and kept at 80° C. for 2 h. The reaction mixturewas cooled to 0° C., quenched carefully with 0.23 mL water and 0.23 mL15% NaOH solution, kept for 10 min, then 0.69 mL water, followed by theaddition of 5 g of Na₂SO₄ solid and stirred for 1 h before filtration.The filtrate was concentrated. The crude product chromatographed(silica, hexanes/MBTE) to give the desired compound (0.32 g, 70%).

Step 339g. To a solution of compound from step 339f (0.32 g, 1.69 mmol)in dichloromethane (3.5 mL) at rt was added pyridine (0.33 mL, 4.3 mmol)and 4-toluenesulfonyl chloride (0.387 g, 2.02 mmol). The reaction wasstirred at rt o/n the water was added. The mixture was stirred for 1 h.After separation, the aqueous phase was extracted with DCM. The combinedorganic phase was washed with 1N HCl, water, NaHCO₃, brine, dried overNa₂SO₄ and concentrated. The crude product chromatographed (silica,hexanes/MBTE) to give the desired compound (0.52 g, 90%).

Step 339h. To a solution of K₂OsO₆.2H₂O (27 mg, 0.073 mmol), (DHQ)₂PHAL(85 mg, 0.109 mmol), K₂CO₃ (0.604 g, 4.37 mmol), and K₃FeCN₆ (1.44 g,4.37 mmol) in t-BuOH (7.0 mL)/water (7.0 mL) at 0° C. was added compoundfrom step 339g (0.50 g, 1.46 mmol) and MeSO₂NH₂ (0.277 g, 2.91 mmol).The reaction was allowed to slowly warm to rt and stirred for 3 days.The mixture was cooled to 0° C. followed by addition of Na₂SO₃. Themixture was stirred 15 mins at 0° C. then 1 hour at rt before partitionwith EtOAc. The aq. phase was back extracted with EtOAc. The combinedorganic was washed with aq. Na₂S₂O₃, water, 1 N HCl, water, 2 M KOH,water, brine, dried (Na₂SO₄), filtered and concentrated. The crudeproduct chromatographed (silica, hexanes/EtOAc), then suspended in MeOH(5.6 mL) for 16 h and filtered to collect the desired product as a whitesolid (0.39 g, 70%).

Step 339i. A solution of compound from step 339 h (0.39 g, 1.03 mmol),intermediate 6 (0.316 g, 1.06 mmol) and K₂CO₃ (0.143 g, 1.03 mmol) inDMF (1.1 mL) was stirred at 70° C. for 16 h. It was diluted with EtOAcand the mixture washed with water, brine, dried over Na₂SO₄, filteredand concentrated. The crude product was chromatographed (silica,hexanes/EtOAc) to give the desired compound as white solid (0.37 g,71%). ESI-MS m/z=503.16, 505.16 [M−H]⁻.

Step 339j. A solution of compound from step 339i (0.37 g, 0.73 mmol) andm-CPBA (0.575 g, 2.56 mmol, 77%) in NMP (3.0 mL) was stirred at rt for24 h. Aqueous Na₂S₂O₃, NaHCO₃ and few drops of Et₃N was added andstirred at rt for 1 h. It was extracted with EtOAc, washed with water,brine, dry over Na₂SO₄, filtered, recrystallized from MeOH to give titlecompound (0.33 g, 84%). ESI-MS m/z=535.15, 537.15 [M−H]⁻.

Example 340

Step 340a. A mixture of compound from step 337c. (3.2 g, 17.6 mmol) andIBX (6.8 g, 24.3 mmol) in DMSO (20 mL) was stirred at 45° C. for 14 h.Aq. Na₂S₂O₃ solution was added at rt and the mixture was extracted withEtOAc. The organic layer was washed with water, brine, dried overNa₂SO₄, filtered and concentrated. The crude product was chromatographed(silica, hexanes/MBTE) to give desired product (2.3 g, 72%).

Step 340b. To a solution of compound from step 340a (2.3 g, 12.8 mmol)in CD₃OD (20 mL) was added MeONa (138 mg, 2.55 mmol) and the mixture wasstirred at rt for 3 h. It was concentrated, and the residue wasredissolved in CD₃OD (20 mL) and stirred for 3 h. The same reactioncycle was repeated two more times and the solution was quenched withD₂O. The mixture was extracted with MBTE. The organic layer was washedwith D₂O and sat. NaCl solution in D₂O, dried over Na₂SO₄, filtered andconcentrated under vacuum to give the desired compound (2.0 g, 85%).

Step 340c. To a solution of LiBH₄ (10.8 mL, 21.6 mmol, 2M solution inTHF) at −40° C. was added compound from step 340b (2.0 g, 10.8 mmol) inMBTE (60 mL). The resulting solution was warmed to 0° C. in 1 h. Thereaction was quenched by slow addition of aq. NH₄Cl then diluted withMBTE and water. The mixture was separated, and the organic layer waswashed with brine. The mixture was dried over Na₂SO₄, filtered andconcentrated. The crude product was chromatographed (silica,hexanes/MBTE) to give the desired compound as white solid (1.4 g, 69%).

Step 340d. To a solution of compound from step 340c (0.216 g, 1.16 mmol)in dichloromethane (1.5 mL) at rt was added pyridine (0.28 mL, 3.48mmol) and 3-nitrobenzenesulfonyl chloride (0.385 g, 1.74 mmol). Thereaction was stirred at rt o/n. Water was added then stirred for 1 h.After separation, the aqueous phase was extracted with DCM. The combinedorganic phase was washed with 1N HCl, water, NaHCO₃, and brine, driedover Na₂SO₄ filtered and concentrated. The crude product chromatographed(silica, hexanes/MBTE) to give the desired compound (0.37 g, 86%).

Step 340e. A solution of compound from step 340d (0.36 g, 0.97 mmol),methyl 4-chloro-3-mercaptobenzoate (0.206 g, 1.02 mmol) and Cs₂CO₃(0.316 g, 0.97 mmol) in DMF (1.1 mL) was stirred at 80° C. for 16 h. Itwas diluted with EtOAc and the mixture washed with water, brine, driedover Na₂SO₄, filtered and concentrated. The crude product waschromatographed (silica, hexanes/EtOAc) to give the desired compound aswhite solid (0.25 g, 69%).

Step 340f. To a solution of compound from step 340e (0.25 g, 0.674 mmol)in THF (3.0 mL) was added LiOH (2.7 mL, 1.35 mmol, 0.5 M solution inwater) and the mixture was stirred at rt for 3 h. The reaction wasquenched by addition of 1 N. HCl. EtOAc and water was added. The mixturewas separated, and the organic layer was washed with brine. The mixturewas dried over Na₂SO₄, filtered and concentrated under vacuum to givethe desired compound as white solid (0.23 g, 96%). ESI-MS m/z=355.24,357.24 [M−H]⁻.

Step 340g. To a solution of compound from step 340f (0.23 g, 0.644mmol), 3,4-difluorobenzene-2,6-D2-amine (0.127 g, 0.967 mmol), DMAP(0.039 g, 0.322 mmol) in DMF (2.5 mL) was added EDC (0.185 g, 0.967mmol) in and stirred at rt for 16 h. It was diluted with EtOAc and themixture washed with water, brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was chromatographed (silica,hexanes/EtOAc) to give the desired compound (0.26 g, 86%). ESI-MSm/z=468.31, 470.31 [M−H]⁻.

Step 340h. To a suspension of compound from step 340g (260 mg, 0.553mmol) and NMO (0.324 g, 2.77 mmol) in acetone-water (2.1 mL/0.3 mL) atrt was added osmium tetroxide (0.28 ml, 0.055 mmol, 5% in water) and themixture was stirred at rt for 20 h. It was quenched with aqueous Na₂SO₃,extracted with EtOAc, washed with water, 1N HCl, NaHCO₃, brine, dry overNa₂SO₄, filtered and concentrated to give a mixture of sulfone andsulfoxide used without further purification.

Step 340i. To a solution of compound from step 340h in NMP (2.5 mL) wasadded m-CPBA (0.41 g, 1.83 mmol, 77%) and stirred at rt for 20 h.Aqueous Na₂S₂O₃, NaHCO₃ and few drops of Et₃N was added and stirred atrt for 1 h. It was extracted with EtOAc, washed with water, brine, driedover Na₂SO₄, filtered and concentrated to five the desired product (0.27g, 96%). ESI-MS m/z=580.33, 582.33 (M+HCO₂)⁻.

Step 340j. A mixture of compound from step 340i (362 mg, 0.675 mmol) andIBX (227 mg, 0.81 mmol) in DMSO (5.0 mL) was stirred at rt for 4 h. Aq.Na₂S₂O₃ solution was added and the mixture was extracted with EtOAc. Theorganic layer was washed with water, brine, dried over Na₂SO₄, filtered,concentrated and purified by prep-HPLC (C18 column, acetonitrile/water)to give title compound (150 mg, 41%). ESI-MS m/z=578.32, 580.32(M+HCO₂)⁻.

Example 341

Step 341a. 1-methyl-1H-pyrrole-2-carboxylic acid (3 g, 23.98 mmol) wasdissolved portionwise in chlorosulfonic acid (12 ml, 179 mmol) in an icebath. The reaction was stirred for 70 min at the same temperature. Themixture was quenched slowly by adding ice/water (100 mL) (veryreactive!!) and stirred for 15 min. The precipitate was filtered, rinsedwith water and the resulting solid was dissolved in EtOAc, dried overNaSO₄. Solvent was removed in vacuo and dried overnight in vacuo to givethe desired compound (3.60 g, 16.10 mmol, 67% yield) as an off-whitesolid.

Step 341b. To a mixture of the compound from step 341a (1 g, 4.47 mmol)in DCM (20 mL) and DMF (0.02 mL) was added oxalyl chloride (11.18 ml,22.36 mmol). The reaction was stirred for 5 h at rt. Solvent was removedin vacuo then chased with benzene (×3) to give the desired compound(1.08 g, 100% yield) as pale yellow solid.

Step 341c. To a solution of the compound from step 341b (400 mg, 1.652mmol) in toluene (15 mL) was added 3,4-difluoroaniline (0.164 ml, 1.652mmol) in toluene (1 mL) at rt. The mixture was heated at 110° C. andstirred for 1 h, and then cooled down to rt and stirred for 16 h. Solidwas filtered off and the resulting filtrate was removed in vacuo, whichwas used without further purification (553 mg, 100% yield).

Step 341d. To a suspension of the compound from step 341c (550 mg, 1.643mmol) in toluene (10 mL) was added triphenylphosphine (2.16 g, 8.22mmol). The reaction was heated to 85° C. and stirred for 6 h. Thereaction was cooled to rt and 10 mL of H₂O was added. Organic layer waswashed with water (5 mL) twice, followed by 1N NaOH. Aq layer wascollected. Aq layer was acidified by 1N HCl to pH4. It turned to a whiteemulsion as HCl was added. It was extracted with EtOAc and the resultingmixture became clear colorless solution. Organic layer was collected,dried over Na₂SO₄ to give desired compound (220 mg, 0.820 mmol, 50%yield) as white solid.

Step 341e. To a solution of the compound from step 341d (130 mg, 0.485mmol) and compound from step 337d (187 mg, 0.505 mmol) in DMF (0.5 mL)was added cesium carbonate (197 mg, 0.606 mmol). The reaction was heatedto 70° C. and stirred for 17 h. The mixture was extracted with EtOAc,dried over Na₂SO₄, and then purified by column chromatography (silica,hexanes/EtOAc) to give desired compound (170 mg, 0.364 mmol, 72% yield)as a white solid.

Step 341f. To a solution of the compound from step 341e (35 mg, 0.075mmol) in NMP (0.3 mL) was added m-CPBA (50.4 mg, 0.225 mmol, 77%) at 0°C. The reaction was slowly warmed to rt and stirred for 15 h. Sat.Na₂S₂O₃ solution and NaHCO₃ solution were added and the resultingmixture was stirred for 1 h at rt. The mixture was extracted with EtOAc,washed with sat. Na₂S₂O₃ solution and NaHCO₃ solution (×2), brine, anddried over Na₂SO₄. The crude material was purified by columnchromatography (silica, hexanes/EtOAc) to give the title compound (24.0mg, 0.048 mmol, 64% yield) as a white solid. ESI-MS m/z=497.52, 499.53[M−H]⁻.

Example 344

Step 344a. To the solution of compound from step 307a (500 mg, 0.71mmol) in 2-methyl-tetrahydrofuran (3 mL) was added(R)-1-aminopropan-2-ol (160 mg, 2.12 mmol) then stirred at 75° C. forone day. The crude was diluted with EtOAc, washed with water twice,brine twice and dried (Na₂SO₄) and concentrated. The crude waschromatographed (silica, MeOH/DC) to give desired compound (255 mg) as amixture of desired with other impurities. ESI-MS m/z=479.27,481.27[M−H]⁻.

Step 344b. To the solution of mixture from step 344a (255 mg, 0.53 mmol)in 2-methyl-tetrahydrofuran (2 mL) was added, CDI (112 mg, 0.69 mmol)and TEA (0.15 mL, 1.06 mmol). The reaction mixture was heated to 50° C.for 1 h before being cooled and concentrated. The crude waschromatographed (silica, EtOAc/hexanes) to give desired compound as amixture with other impurities. ESI-MS m/z=505.26, 507.26 [M−H]⁻.

Step 344c. The compound from step 344b was treated with the conditionsdescribed in 130b and purified by prep-HPLC (C-18, Acetonitrile/water)to offer the title compound as a white solid. ESI-MS m/z=537.26, 539.26[M−H]⁻.

Example 345

Step 345a. To a solution of the compound from step 182 (1.046 g, 2.100mmol) in CH₂Cl₂ (21 mL) at rt was added triethylamine (0.586 ml, 4.20mmol) and Ac₂O (0.238 ml, 2.52 mmol), then the mixture was kept at rtfor overnight. Then the reaction mixture was partitioned between NaHCO₃aqueous solution and CH₂Cl₂. The combined organic phases were dried overNa₂SO₄, concentrated and the crude product was purified by flash columnchromatography to give a mixture (415 mg) of two inseparable monoacylated products. ESI-MS m/z=584.13, 586.13 [M+HCO₂]⁻.

Step 345b. To a solution of the compound from step 345a (415 mg, 0.768mmol) in CH₂Cl₂ was added 2-iodoxylbenzoic acid (430 mg, 1.54 mmol). Themixture was kept at rt overnight then saturated Na₂S₂O₃ aqueous solutionwas added. The mixture was partition between EtOAc and water. Thecombined organic phases were washed with brine, dried over Na₂SO₄ andconcentrated. The resulting crude product was chromatographed (silica,hexanes/EtOAc) to give the desired product (39 mg, 8.2% over 2 steps) asa white solid. ESI-MS m/z=582.12, 584.12 [M+HCO₂]⁻.

Step 345c. To a solution of the compound from Step 345b (39.1 mg, 0.073mmol) in THF (0.3 mL) and MeOH (1.1 mL) at rt was added K₂CO₃ (10 mg,0.073 mmol). Then the mixture was kept at rt for 1 h. The reactionmixture was diluted with MTBE, washed with water, dried over Na₂SO₄ andconcentrated to give the desired crude product (19 mg, 53%) as a whitesolid, which was taken into next step without further purification.ESI-MS m/z=540.11, 542.11 [M+HCO₂]⁻.

Step 345d. To a solution of the compound from Step 345c (19 mg, 0.038mmol) in CH₂Cl₂ (1.9 mL) at rt was added m-CPBA (34.3 mg, 0.153 mmol,77%) and stirred at rt overnight. The reaction was quenched withsaturated Na₂S₂O₃ aqueous solution and NaHCO₃ aqueous solution. Thereaction mixture was partitioned between EtOAc and aqueous phase. Thecombined organic phases were washed with brine, dried over Na₂SO₄ andconcentrated. The resulting crude product was chromatographed to givethe desired product (11 mg, 29% over 2 steps) as a white solid. ESI-MSm/z=572.09, 574.09 [M+HCO₂]⁻.

Example 346

Step 346a. To a solution of ethynylcyclopropane (1.864 ml, 22.03 mmol)in THF (4.50 ml) was added n-BuLi (8.81 ml, 22.03 mmol, 2.5M in THF) at−78° C. The resulting mixture was stirred for 1 h at the sametemperature. A solution of compound from step int 2a (2.0 g, 14.68 mmol)in THF (9 ml) was added into the reaction at −78° C. The resulting lightyellow solution was slowly warmed to rt and stirred for 2 h. Sat. NH₄Clsolution was added. The mixture was extracted with MTBE, dried overNa₂SO₄ to give 2.95 g (99% yield) of the desired compound as yellow oil,which was used without further purification.

Step 346b. To a solution of the compound from step 346a (2.97 g, 14.68mmol) in dioxane (122 mL) and water (25 mL) at 5° C. were added2,6-lutidine (3.42 ml, 29.4 mmol), sodium periodate (10.99 g, 51.4mmol). OsO₄ (0.921 ml, 0.073 mmol, 2.5% in t-BuOH) was added and theresulting mixture was stirred for 15 h at rt. Na₂S₂O₃ (50 mL) and EtOAc(100 mL) were added. The mixture was stirred for 30 min then filtered.Solid was washed with EtOAc (×3). Filtrate was collected and washed with0.5N HCl (×4). Aq layer was back extracted with EtOAc and the combinedorganic layer was dried over Na₂SO₄. The crude material waschromatographed (silica, hexanes/acetone) to give the desired compound(2.25 g, 11.01 mmol, 75% yield) as a light yellow oil.

Step 346c. To a solution of LiBH₄ (13.77 ml, 27.5 mmol, 2M in THF) inMTBE (22.03 ml) at −50° C. was added a solution of the compound fromstep 346b (2.25 g, 11.01 mmol) in MTBE (5 mL). The reaction was stirredat −50° C. for 3 h. NH₄Cl (50 mL) was added. The mixture was extractedwith EtOAc (100 mL), washed with brine, dried over Na₂SO₄ andchromatographed (silica, hexanes/EtOAc) to give the desired compound(1.62 g, 7.85 mmol, 71% yield) as a white solid.

Step 346d. To a mixture of LAH (13.77 ml, 13.77 mmol, 1M in THF) andNaOMe (0.074 g, 1.377 mmol) in DME (15 mL) at rt was added a solution ofthe compound from step 346c (1.42 g, 6.88 mmol) in DME (2 mL). Thereaction was heated to 80° C. and stirred for 3 h. The reaction wascooled down to 0° C., quenched with water and 1N NaOH solutioncarefully. The mixture was filtered. The filtrate was extracted withMTBE, dried over Na₂SO₄. Recrystallization of the resulting materialwith MTBE and Hex to give the desired compound (1.30 g, 6.24 mmol, 91%yield) as a white solid.

Step 346e. To a solution of the compound from step 346d (1.6 g, 7.68mmol) in DCM (10 ml) was added pyridine (1.243 ml, 15.36 mmol) at 0° C.4-methylbenzenesulfonyl chloride (1.904 g, 9.99 mmol) was added. Themixture was slowly warmed to rt and stirred for 16 h. Water was added,and the mixture was extracted with DCM, dried over Na₂SO₄. The crudematerial was purified by column chromatography (silica, hexanes, EtOAc)to give the desired compound (2.10 g, 5.79 mmol, 75% yield) as acolorless oil.

Step 346f. To a mixture of t-BuOH (29.0 ml) and water (29.0 ml) at 0° C.was added potassium osmate dihydrate (0.064 g, 0.174 mmol), (DHQ)₂PHAL(0.203 g, 0.261 mmol), potassium hexacyanoferrate(III) (5.72 g, 17.38mmol) and potassium carbonate (2.402 g, 17.38 mmol), followed bymethanesulfonamide (3.31 g, 34.8 mmol) and the compound from step 346e(2.1 g, 5.79 mmol). The reaction was warmed to rt slowly and stirred for50 h. Na₂SO₃ (3.7 g) was added at 0° C. and the resulting mixture wasstirred for 1 h at rt. EtOAc was added, solid was filtered throughCelite, and washed with EtOAc (×2). Organic layer was extracted withEtOAc, and washed with 1N HCl (×3), followed by 2N K₂CO₃ solution andbrine, and dried over Na₂SO₄ to give 1.85 g (4.67 mmol, 81% yield) ofthe desired product as an off-white solid, which was used withoutfurther purification.

Step 346g. To a solution of the compound from step 346f (1.85 g, 4.67mmol) in DMF (15.55 ml) was added K₂CO₃ (0.632 g, 4.57 mmol) at rt.4-chloro-N-(3,4-difluorophenyl)-3-mercaptobenzamide (1.468 g, 4.90 mmol)was added. The resulting mixture was heated to 75° C. and stirred for 15h. The reaction was cooled to rt, water was added, and extracted withEtOAc (×3), washed with brine, dried over Na₂SO₄. The crude material waschromatographed (silica, hexanes/EtOAc) to give the desired compound(1.91 g, 3.64 mmol, 75% yield) as an off-white solid.

Step 346h. To a solution of the compound from step 346g (1.91 g, 3.64mmol) in NMP (10 mL) was added m-CPBA (2.451 g, 10.93 mmol, 77%) at 0°C. The mixture was warmed to rt and stirred for 15 h. The reaction wasquenched with sat. Na₂S₂O₃ solution and NaHCO₃ solution, stirred for 1h. The mixture was extracted with EtOAc, washed with sat. Na₂S₂O₃solution and NaHCO₃ solution (×2), brine, dried over Na₂SO₄. The crudematerial was chromatographed (silica, hexanes/acetone) to give thedesired compound (1.26 g, 2.27 mmol, 42% yield) as white solid. ESI-MSm/z=555.02, 557.02 [M−H]⁻.

Example 347

Step 347a. To a solution of 3-methylbut-1-yne (2.253 ml, 22.03 mmol) inTHF (4.50 ml) was added n-BuLi (8.81 ml, 22.03 mmol, 2.5M in THF) at−78° C. The resulting mixture was stirred for 1 h at the sametemperature. A solution of compound from step int 2a (2.0 g, 14.68 mmol)in THF (10 ml) was added into the reaction at −78° C. The resultinglight yellow solution was slowly warmed to rt and stirred for 2 h. Sat.NH₄Cl solution was added. The mixture was extracted with MTBE, driedover Na₂SO₄ to give 3.0 g (99% yield) of the desired compound as ayellow oil, which was used without further purification.

Step 347b. To a solution of the compound from step 347a (3.0 g, 14.68mmol) in dioxane (122 mL) and water (25 mL) at 5° C. were added2,6-lutidine (3.42 ml, 29.4 mmol), sodium periodate (10.99 g, 51.4mmol). Osmium tetroxide (0.921 ml, 0.073 mmol, 2.5% in tBuOH) was addedand the resulting mixture was stirred for 16 h at rt. Na₂S₂O₃ (50 mL)and EtOAc (100 mL) were added. The mixture was stirred for 30 min thenfiltered. Solid was washed with EtOAc (×3). Filtrate was collected,washed with 0.5N HCl (×4). Aq layer was back extracted with EtOAc andcombined organic layer was dried over Na₂SO₄. The crude material waschromatographed (silica, hexanes/acetone) to give the desired compound(1.60 g, 7.76 mmol, 53% yield) as a light yellow oil.

Step 347c. To a solution of LiBH₄ (9.70 ml, 19.39 mmol, 2M in THF) inMTBE (15.51 ml) at −50° C. was added a solution of the compound fromstep 347b (1.60 g, 7.76 mmol) in MTBE (5 mL). The reaction was stirredat −50° C. for 3 h. NH₄Cl (50 mL) was added. The mixture was extractedwith EtOAc (100 mL), washed with brine, dried over Na₂SO₄. The crudematerial was chromatographed (silica, hexanes/EtOAc) to give the desiredcompound (1.16 g, 5.58 mmol, 72% yield) as a white foaming solid.

Step 347d. To a mixture of LAH (11.16 ml, 11.16 mmol, 1M in THF) andsodium methoxide (0.060 g, 1.116 mmol) in DME (15 mL) at rt was added asolution of the compound from step 347c (1.162 g, 5.58 mmol) in DME (2mL). The reaction was heated to 80° C. and stirred for 3 h. The reactionwas cooled down to 0° C., quenched with water and 1N NaOH solutioncarefully. The mixture was filtered. The filtrate was extracted withMTBE, dried over Na₂SO₄. Recrystallization of the resulting materialwith MTBE and Hex to give the desired compound (1.06 g, 5.02 mmol, 90%yield) as a white solid.

Step 347e. The desired compound was obtained from the compound of step347d following the procedure described in example 346e as cloudy oil(1.51 g, 4.14 mmol, 87% yield).

Step 347f. The desired compound was obtained from the compound of step347e following the procedure described in example 346f as off-whitesolid (1.01 g, 2.53 mmol, 61% yield).

Step 347g. The desired compound was obtained from the compound of step347f following the procedure described in example 346g as off-whitesolid (0.87 g, 1.65 mmol, 65% yield).

Step 347h. The desired compound was obtained from the compound of step347g following the procedure described in example 346h as white solid(0.74 g, 1.32 mmol, 80% yield). ESI-MS m/z=557.03, 559.02 [M−H]⁻.

Example 348

Step 348a. To a solution of compound from example 82a (50 mg, 0.111mmol) in DCE (2 ml) at rt were added tert-butyl2-oxo-5-vinyloxazolidine-3-carboxylate (71.1 mg, 0.333 mmol) andGrubbs-Hoveyda 2^(nd) generation catalyst (6.96 mg, 0.011 mmol). Themixture was degased with bubbling N₂ for 5 min and heated to 60° C. andstirred for 15 h. The reaction was cooled to rt. Water was added. Themixture was extracted with DCM, dried over Na₂SO₄. The crude materialwas chromatographed (silica, hexanes/EtOAc) to give the desired compound(45 mg, 0.071 mmol, 64% yield) as an off-white solid.

Step 348b. To a solution of the compound from step 348a (45 mg, 0.071mmol) in acetone (3 ml) and water (0.8 ml) was added NMO (33.2 mg, 0.283mmol), OsO₄ (178 μl, 0.014 mmol, 2.5% in t-BuOH) at rt. The reaction wasstirred for 16 h. It was quenched with sat. Na₂S₂O₃ solution andextracted with EtOAc, washed with brine, and dried over Na₂SO₄. Thecrude material was used without further purification.

Step 348c. To a solution of the compound from step 348b (50 mg, 0.071mmol) in DCM (1 ml) was added TFA (0.027 ml, 0.355 mmol) at rt. Thereaction was stirred for 2 h. Solvent removed. The mixture was extractedwith DCM, washed with sat. NaHCO₃ solution, dried over Na₂SO₄. The crudematerial was purified by column chromatography (silica, MeOH/DCM) togive the desired compound (2:1 isomeric mixture, 14.5 mg, 0.024 mmol,34% yield) as off-white solid. ESI-MS m/z=600.02, 602.02 [M−H]⁻.

The following examples were prepared using procedures similar to thosedescribed above:

Ex- ESIMS (M − H)⁻ am- or ple Structure (M + H)⁺ 2

587.12, 589.12 8

672.13, 674.13 12

569.09, 571.09 13

573.09, 575.09 15

599.123, 601.121 16

714.19, 716.19 17

714.19, 716.18 22

641.13, 643.13 (M + HCO₂)⁻. 23

702.15, 704.15 (M + HCO₂)⁻ 24

675.13, 677.13 (M + HCO₂)⁻ 25

603.10, 605.10 30

532.05 31

444.08, 446.06537.20 [M + NH₄]⁺. 39

605.07, 607.07 40

639.08, 641.08 41

641.13, 643.13 (M + NCO₂)⁻ 43

494.20 44

466.20 45

494.20 [M + NH₄]⁺ 46

486.15 [M + H]⁺, 503.15 [M + NH₄]⁺. 47

450.20 48

630.12, 632.12 49

646.11, 648.11 50

658.16, 660.16 53

584.8, 586.8 54

586.8, 588.8 55

586.8, 588.8 57

616.8, 618.8 58

568.8, 570.8 59

675.13, 677.13 (M + NCO₂)⁻ 60

606.11, 608.11 62

546.08, 548.08 63

576.09, 578.09 65

602.8, 604.8 66

627.11, 629.11 (M + NCO₂)⁻ 67

661.12, 663.12 (M + HCO₂)⁻ 68

650.11, 651.11 (M + HCO₂)⁻ 69

484.20 [M + H)⁺, 501.20 [M + NH₄]⁺ 71

600.8, 602.8 72

598.8, 600.8 73

598.8, 600.8 75

712.18, 714.18 77

760.20, 762.20 [M + NCO₂]⁻ 79

718.16, 720.16 [M + HCO₂]⁻ 80

676.14, 678.14 (M + HCO₂)⁻ 81

676.14, 678.14 (M + HCO₂)⁻ 83

673.13, 675.13 84

687.15, 689.15 85

614.09, 616.09 86

630.13, 632.13 87

598.8, 600.8 88

595.8, 597.8 89

612.8, 614.8 90

612.8, 614.8 91

612.8, 614.8 92

584.7, 586.7 93

626.8, 628.8 94

610.8, 612.8 95

614.09, 616.09 96

646.12, 648.12 97

614.10, 616.10 98

560.11, 562.11 99

605.15, 606.15 100

548.00 101

546.15 102

547.20 103

526.15 104

482.15 105

487.15 [M + NH₄]⁺ 107

702.15, 704.15 110

584.8, 586.8 111

598.8, 600.8 112

586.8, 588.8 113

586.8, 588.8 114

586.8, 588.8 115

600.8, 602.8 116

612.8, 614.8 117

598.8, 600.8 118

600.8, 602.8 119

600.8, 602.8 122

590.12, 592.12 123

516.08, 518.08 126

601.13, 603.13 127

612.11, 614.11 128

658.12, 660.12 [M − HCO₂]⁻ 129

601.13, 603.12 131

560.11, 562.11 132

673.0, 675.0547.05 133

547.20 134

468.15 135

510.15 138

611.8, 613.8 139

614.8, 616.8 140

600.8, 602.8 142

614.13, 616.13 143

612.11, 614.11 145

471.07, 473.07 146

525.12, 527.12 147

586.10, 588.10 148

663.14, 665.14 [M + HCO₂]⁻ 149

480.10, 482.10 151

516.08, 518.08 152

704.18, 706.18 154

662.13, 664.13 155

601.14, 603.14 157

553.15 158

553.05 159

614.10 160

558.15 161

565.15, 567.15 162

565.15, 567.15 165

540.30 166

482.20 167

580.2 168

596.2 169

571.2 170

585.2 171

583.2 172

528.10, 530.10 173

528.10, 530.10 176

542.12, 544.12 177

542.12, 544.12 178

572.13, 574.13 179

572.13, 574.13 184

557.15 185

571.25 186

571.20 187

585.20, 587.15 188

585.20, 587.15 189

585.20, 587.15 190

571.20 191

599.30 192

583.20 193

526.05 194

471.95 195

571.00 196

571.00 197

530.10 198

530.00 199

502.05, 504.05 200

443.95 201

458.00, 460.00 207

473.95 208

501.95 209

501.95 211

413.95 212

436.05 213

436.30 214

434.20 215

510.00 216

484.00 217

436.05 218

512.05 219

462.00 220

429.95 221

436.25 222

498.05 223

498.00 224

500.05 225

500.05, 502.05 226

444.00 227

424.00 228

514.05 229

514.10 230

488.00 231

512.05 232

490.05 233

428.00 234

488.00 235

470.00 236

470.00 237

484.05 238

484.05 239

440.00 240

444.00 241

258.00 242

471.95 243

458.00 244

529.00 245

503.10 246

543.00 247

517.15 248

542.95 249

517.15 250a

442.05 250b

444.05 251

430.05 252a

414.05 252b

414.05 253a

499.10 253b

499.10 254

473.10 255

515.05 256a

485.15 256b

485.15 257a

513.10 257b

513.15 258

487.15 260

425.95 280

292.13, 294.13 [M − H]⁻ 282

564.29, 566.29 294

621.13, 623.13 [M + HCO₂]⁻ 294a

621.13, 623.13 [M + HCO₂]⁻ 294b

621.13, 623.13 [M + HCO₂]⁻ 295

621.13, 623.13 [M + HCO₂]⁻ 295a

621.13, 623.13 [M + HCO₂]⁻ 295b

621.13, 623.13 [M + HCO₂]⁻ 296

621.13, 623.13 [M + HCO₂]⁻ 296a

621.13, 623.13 [M + HCO₂]⁻ 296b

621.13, 623.13 [M + HCO₂]⁻ 297a

625.11, 627.11 [M + HCO₂]⁻ 297b

625.11, 627.11 [M + HCO₂]⁻ 299

625.11, 627.10 [M + HCO₂]⁻ 300

675.10, 677.10 [M + HCO₂]⁻ 301

657.32, 659.32 [M + HCO₂]⁻ 302

613.24, 615.23 [M + HCO₂]⁻ 302a

613.24, 615.23 [M + HCO₂]⁻ 302b

613.24, 615.23 [M + HCO₂]⁻ 303

597.27, 599.26 [M + HCO₂]⁻ 304

539.16, 541.16 [M − H]⁻ 305

8 624.10, 626.10 [M + CO₂]⁻ 306

553.26, 5552.6 [M − H]⁻ 310

610.12, 612.12 [M + HCO₂]⁻ 311

610.12, 612.12 [M + HCO₂]⁻ 312

629.11, 31.11 [M + HCO₂]⁻ 313

659.31, 661.31 [M + HCO₂]⁻ 324

558.14 [M + HCO₂]⁻ 325

514.11 [M − H]⁻ 326

576.13 [M + HCO₂]⁻ 335

588.30, 590.30 [M + HCO₂]⁻ 338

580.15, 582.15 [M + HCO₂]⁻ 342

567.19, 569.19 [M − H]⁻ 343

548.23, 550.23 [M − H] 349

657.11, 659.11 [M + HCO₂]⁻ 350

657.11, 659.11 [M + HCO₂]⁻ 351

651.14, 653.14 [M + HCO₂]⁻ 352

637.12, 639.12 [M + HCO₂]⁻

The following examples are prepared using procedures similar to thosedescribed above:

Biological Activity

Methods: HepAD38 cells are maintained as previously reported (Ladner etal, Antimicrob. Agents Chemother. 1997, 4, 1715). Briefly, cells arepassaged upon attaining confluency in DMEM/F12 media in the presence of10% FBS, Penn/Strep, 250 μg/mL G418, and 1 ug/ml tetracycline. Novelcompounds are screened by first washing cells three times with PBS toremove tetracycline, and plating in 96 well plates at 35,000 cells/well.Compounds dissolved in DMSO are then diluted 1:200 into wells containingcells. Five days after compound addition, material is harvested foranalysis. For an extended 8 days analysis, cells are plated and treatedas described above, but media and compound are refreshed on d2 and d5post initial treatment.

On harvest day, virion DNA is obtained by lysing with Sidestep Lysis andStabilization Buffer and then quantified via quantitative real time PCR.Commercially available ELISA kits are used to quantitate the viralproteins HBsAg (Alpco) or HbeAg (US Biological) by following themanufacturer's recommended protocol after diluting samples to match thelinear range of their respective assays. Irrespective of readout,compound concentrations that reduce viral product accumulation in thecell lysates or supernatants by 50% relative to no drug controls (EC₅₀)are reported; EC₅₀ ranges are as follows: A<0.104; B 0.1-0.2 μM; C>0.2μM.

Compound toxicity is evaluated by seeding cells at 15,000 cells/well andtreating with compound as described above. Three days after compoundaddition, cells are treated with ATPLite reagent and compoundconcentrations that reduce total ATP levels in wells by 50% relative tono drug controls (CC₅₀) are reported; CC₅₀ ranges are as follows: A>25μM; B 10-25 μM; C<10 μM.

TABLE 1 Summary of Activities Compd. HepAD38 Compd. HepAD38 Number EC₅₀(μM) Number EC₅₀ (μM)  1 A  2 B  3 A  4 A  5 A  6 A  7 A  8 C  9 A  10 A 11 A  12 A  13 A  14 A  15 A  16 A  17 A  18 A  19 C  20 A  21 A  22 A 23 A  24 C  25 C  26 A  27 C  28 A  29 C  30 A  31 B  32 C  33 C  34 A 35 A  36 A  37 B  38 C  39 A  40 C  41 A  42 A  43 C  44 C  45 C  46 C 47 B  48 A  49 C  50 A  51 A  52 A  53 A  54 A  55 A  56 B  57 B  58 A 59 B  60 B  61 A  62 A  63 A  64 B  65 A  66 A  67 C  68 A  69 A  70 A 71 A  72 A  73 A  74 B  75 A  76 A  77 C  78 C  79 C  80 A  81 A  82 A 83 C  84 C  85 C  86 A  87 A  88 A  89 A  90 A  91 A  92 A  93 A  94 A 95 C  96 B  97 B  98 A  99 A 100 A 101 C 102 C 103 A 104 C 105 A 106 A107 C 108 A 109 A 110 A 111 A 112 A 113 A 114 A 115 A 116 A 117 A 118 A119 C 120 C 121 A 122 A 123 A 124 A 125 A 126 A 127 C 128 C 129 A 130 A131 A 132 C 133 C 134 C 135 A 136 A 137 A 138 A 139 C 140 C 141 B 142 B143 C 144 B 145 C 146 C 147 A 148 B 149 A 150 A 151 A 152 C 153 B 154 C155 A 156 A 157 A 158 A 159 A 160 C 161 A 162 A 163 A 164 A 165 A 166 A167 A 168 A 169 B 170 A 171 C 172 A 173 A 174 A 175 A 176 A 177 A 178 A179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188 A 189 A 190 A191 A 192 A 193 A 194 B 195 C 196 C 197 C 198 B 199 C 200 C 201 C 202 A203 A 204 B 205 C 206 B 207 C 208 C 209 C 210 A 211 C 212 C 213 C 214 C215 A 216 B 217 C 218 A 219 C 220 C 221 C 222 B 223 B 224 B 225 B 226 C227 C 228 C 229 C 230 C 231 C 232 C 233 C 234 C 235 C 236 C 237 C 238 C239 C 240 C 241 C 242 C 243 C 244 C 245 C 246 C 247 C 248 C 249 C 250a C250b C 251 C 252a C 252b C 253a C 253b C 254 C 255 C 256a C 256b C 257aC 257b C 258 C 260 C 272 A 279 A 280 A 281 C 282 A 283 B 284 A 284a A284b A 285 A 285a A 285b A 286 B 287 C 288 A 289 A 290 A 291 A 291a A291b A 292 C 293 A 294 A 294a A 294b A 295 A 296 A 296a A 296b A 297 A298 A 299 A 300 C 301 A 302 A 303 A 304 A 305 A 306 A 307 B 308 A 309 B310 C 311 C 312 C 313 A 314 A 315 C 316 C 317 A 318 C 319 A 320 A 321 A322 A 323 B 324 A 325 A 326 A 327 B 328 B 329 A 330 C 331 A 332 A 333 A334 A 335 A 336 A 337 C 338 A 341 C 342 A 343 A 344 A 345 A 346 347 348A 349 B 350 A

TABLE 2 Summary of Cytotoxicity Compd. ATPlite Compd. ATPlite NumberCC₅₀ (μM) Number CC₅₀ (μM)  1 >3    4 >12.5   5 >3    9 >6.25  10 >12.5  11 >6.25  12 >3    13 >6.25  36 A  39 >6.25  41 >6.25  52 A  53 >6.25 54 A  55 A  58 >12.5   61 >6.25  62 >12.5   66 B  68 A  70 A  71 >3   72 >3    73 >6.25  88 >6.25  89 >6.25  90 >6.25  91 B  92 >6.25 93 >6.25 111 >3   112 >6.25 113 >6.25 114 >6.25 116 >3   117 >6.25 122A 125 >6.25 126 >6.25 129 A 130 >12.5  131 >12.5  135 C 136 >12.5 137 >6.25 149 A 150 A 151 A 152 A 155 A 162 >6.25 163 A 167 >12.5  168 B172 A 173 >6.25 176 >6.25 177 >6.25 178 A 179 A 180 A 182 A 183 A185 >12.5  186 >12.5  187 >12.5  188 >12.5  189 >12.5  191 A 192 >12.5 193 A 215 A 218 B 272 A 279 A 280 A 284b A 285a A 285b A 289 A 290 A 291A 294 A 296 A 302 A 303 A 308 A 317 A 319 A 325 A 326 A 329 A 331 A 332A 335 A 338 A 343 A 344 A 345 A

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed is:
 1. A method of treating a hepatitis B virusinfection in a subject in need thereof, comprising administering to thesubject a therapeutically effective amount of a compound represented byFormula (XVII),

wherein R₂₁, R₂₁′ and R₂₁″ are independently selected from hydrogen,fluorine, methyl, difluoromethyl, and trifluoromethyl; R₃₉ is hydroxyl;and R₄₀ is —[C(R₄₁)(R₄₂)]_(q)—R₄₃, wherein q is 2; R₄₁ is hydrogen, andR₄₂ is hydroxyl; or R₄₁ and R₄₂ of one C(R₄₁)(R₄₂) group together forman oxo group; and R₄₃ is methyl.
 2. The method of claim 1, wherein thecompound is selected from the compounds set forth below: CompoundStructure 108

109

136

137

180

181

182

183

331

345


3. The method of claim 2, wherein the compound has the structure


4. The method of claim 2, wherein the compound has the structure


5. The method of claim 2, wherein the compound has the structure


6. The method of claim 2, wherein the compound has the structure


7. The method of claim 2, wherein the compound has the structure


8. The method of claim 2, wherein the compound has the structure


9. The method of claim 2, wherein the compound has the structure


10. The method of claim 2, wherein the compound has the structure


11. The method of claim 2, wherein the compound has the structure


12. The method of claim 2, wherein the compound has the structure


13. The method of claim 1, wherein R₄₁ is hydrogen, and R₄₂ is hydroxyl.